Gating of auditory evoked potentials and prepulse inhibition - Webs
Gating of auditory evoked potentials and prepulse inhibition - Webs
Gating of auditory evoked potentials and prepulse inhibition - Webs
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GATING OF AUDITORY EVOKED POTENTIALS<br />
AND PREPULSE INHIBITION:<br />
AN ANIMAL MODELING APPROACH<br />
DISTINCT RODENT GENOTYPES<br />
AND THE ROLE OF DOPAMINE<br />
NATASJA DE BRUIN<br />
1
2<br />
GATING OF AUDITORY EVOKED POTENTIALS<br />
AND PREPULSE INHIBITION:<br />
AN ANIMAL MODELING APPROACH<br />
DISTINCT RODENT GENOTYPES AND<br />
THE ROLE OF DOPAMINE
The studies described in this thesis were carried out at<br />
� NICI, Department <strong>of</strong> Psychoneuropharmacology,<br />
University <strong>of</strong> Nijmegen, The Netherl<strong>and</strong>s<br />
� NICI, Department <strong>of</strong> Comparative <strong>and</strong> Physiological<br />
Psychology, University <strong>of</strong> Nijmegen, The Netherl<strong>and</strong>s<br />
� Health Sciences Center, Department <strong>of</strong> Psychiatry,<br />
University <strong>of</strong> Colorado, Denver, Colorado, USA<br />
Cover: Jim DeLutes, http://www.JDLphotos.com<br />
On the bank <strong>of</strong> a small pond just east <strong>of</strong> Boulder, Colorado.<br />
"As if you are on the front row seats to an incredible<br />
performance by nature. "<br />
ISBN 90-9014705-5<br />
© N.M.W.J. de Bruin, Nijmegen, The Netherl<strong>and</strong>s<br />
All rights reserved. No part <strong>of</strong> this publication may be<br />
reproduced, stored in a retrieval system, or transmitted in<br />
any means, mechanically, by photocopying, recording, or<br />
otherwise, without permission from the publisher.<br />
Printed by PrintPartners Ipskamp, Enschede<br />
3
4<br />
GATING OF AUDITORY EVOKED POTENTIALS<br />
AND PREPULSE INHIBITION:<br />
AN ANIMAL MODELING APPROACH<br />
DISTINCT RODENT GENOTYPES AND<br />
THE ROLE OF DOPAMINE<br />
Een wetenschappelijke proeve op het gebied van de<br />
MEDISCHE WETENSCHAPPEN<br />
PROEFSCHRIFT<br />
Ter verkrijging van de graad van doctor<br />
aan de Katholieke Universiteit Nijmegen,<br />
volgens besluit van het College van Decanen<br />
in het openbaar te verdedigen op<br />
ma<strong>and</strong>ag 28 mei 2001<br />
des namiddags om 13.30 uur precies<br />
door<br />
Natasja Maria Wilhelmina Johanna de Bruin<br />
Geboren 20 juli 1970 te Tilburg<br />
NICI<br />
Nijmeegs Instituut voor Cognitie en Informatie
Promotores: Pr<strong>of</strong>. A.R. Cools<br />
Pr<strong>of</strong>. A.M.L. Coenen<br />
Co-Promotores: Dr. B.A. Ellenbroek<br />
Dr. E.L.J.M. Van Luijtelaar<br />
Manuscriptcommissie: Pr<strong>of</strong>. M.J. Zwarts (Voorzitter)<br />
Pr<strong>of</strong>. M.N. Verbaten (UU)<br />
Dr. R.J. Verkes<br />
Voor mijn ouders, Ans en Jan<br />
5
CHAPTER 1 General Introduction<br />
CHAPTER 2 Sensory gating <strong>of</strong> <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong> in<br />
rats: effects <strong>of</strong> repetitive stimulation <strong>and</strong> the interstimulus<br />
interval<br />
N.M.W.J. de Bruin, B.A. Ellenbroek, W.J. van Schaijk, A.R. Cools,<br />
A.M.L. Coenen, E.L.J.M. van Luijtelaar<br />
Biological Psychology 55 (2001) 95–213<br />
CHAPTER 3 Dopamine characteristics in different rat<br />
genotypes: the relation to absence epilepsy<br />
N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, S.J. Jansen, A.R. Cools,<br />
B.A. Ellenbroek<br />
Neuroscience Research 38 (2000) 165–173<br />
CHAPTER 4 Dopamine characteristics in rat genotypes with<br />
distinct susceptibility to epileptic activity: apomorphineinduced<br />
stereotyped gnawing <strong>and</strong> novelty / amphetamineinduced<br />
locomotor stimulation<br />
N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, A.R. Cools, B.A.<br />
Ellenbroek<br />
Behavioural Pharmacology 12 (2001) 517–525<br />
CHAPTER 5 Auditory information processing in rat<br />
genotypes with different dopaminergic properties<br />
N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, A.R. Cools, B.A.<br />
Ellenbroek<br />
Psychopharmacology 156 (2001) 352–359<br />
CHAPTER 6 Hippocampal <strong>and</strong> cortical sensory gating in<br />
rats: effects <strong>of</strong> quinpirole microinjections in nucleus<br />
accumbens core <strong>and</strong> shell<br />
N.M.W.J. de Bruin, B.A. Ellenbroek, E.L.J.M. van Luijtelaar, A.R.<br />
Cools, K.E. Stevens<br />
Neuroscience 105 (2001) 169–180<br />
CHAPTER 7 Differential effects <strong>of</strong> ketamine on gating <strong>of</strong><br />
<strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong> <strong>and</strong> <strong>prepulse</strong> <strong>inhibition</strong> in rats<br />
N.M.W.J. de Bruin, B.A. Ellenbroek, A.R. Cools, A.M.L. Coenen,<br />
E.L.J.M. van Luijtelaar<br />
Psychopharmacology 142 (1999) 9–17<br />
CHAPTER 8 General Discussion<br />
6<br />
7<br />
54<br />
73<br />
82<br />
91<br />
99<br />
111<br />
120
Adequate information processing is essential for normal functioning.<br />
Information processing disturbances occur in many neurological <strong>and</strong><br />
psychiatric diseases. These deficits have become apparent in schizophrenic<br />
patients. McGhie <strong>and</strong> Chapman (1961) proposed that symptoms <strong>of</strong><br />
schizophrenia could be understood as a disturbance in the filtering or gating<br />
<strong>of</strong> sensory stimuli <strong>and</strong> irrelevant thoughts from intruding into conscious<br />
awareness. Theoretically, impairments in gating may lead to sensory<br />
overload, cognitive fragmentation, loss <strong>of</strong> ego-boundaries, <strong>and</strong> appraisal in<br />
schizophrenic-spectrum patients (McGhie <strong>and</strong> Chapman 1961; Venables<br />
1964; Braff <strong>and</strong> Geyer 1990).<br />
"It is difficult to maintain integrity <strong>of</strong> thought when sensory<br />
information is unchecked, <strong>and</strong> floods our attentional resources.<br />
The inability to appropriately inhibit, or gate, sensory<br />
information is formally recognized within the Diagnostic <strong>and</strong><br />
Statistical Manual as a clinical feature associated with<br />
schizophrenia (APA, 1994)." (Swerdlow, 1996)<br />
With 'gating' in this thesis, we refer to the normal <strong>inhibition</strong> <strong>of</strong><br />
response that occurs when an acoustic stimulus is preceded by<br />
another stimulus at a short interval (
1.1. DOPAMINERGIC SYSTEM<br />
1.1.1. STRIATUM AND SUBDIVISIONS<br />
The striatum is comprised <strong>of</strong> the dorsal caudate-putamen (CPu) <strong>and</strong> the<br />
ventral nucleus accumbens (NAC) (see Figure 1.1.). Therefore, these areas<br />
have also been termed dorsal <strong>and</strong> ventral striatum. Additionally, the rat<br />
striatum has been subdivided into patch (striosomes) <strong>and</strong> matrix<br />
compartments (Bolam et al 1988, Gerfen 1985, Kawaguchi et al 1989; for<br />
review see Gerfen 1992b). Besides in rats, this mosaic patch-matrix<br />
organization has been found in primates (Gerfen et al 1985) <strong>and</strong> in the cat<br />
(Jimenez-Castellanos <strong>and</strong> Graybiel 1989) as well. These subdivisions have<br />
been found to be biochemically <strong>and</strong> developmentally distinct <strong>and</strong> posses<br />
different laminar <strong>and</strong> regional cortical inputs (Donoghue <strong>and</strong> Herkenham<br />
1986, Gerfen 1984, 1989; Gerfen et al 1987b). Throughout the majority <strong>of</strong><br />
both the dorsal <strong>and</strong> ventral striatum this patch-matrix organization is found.<br />
However, within the medial part <strong>of</strong> the NAC these patterns are not as distinct<br />
(Voorn et al 1989; Jongen-Relo et al 1993). Finally, the NAC has been divided<br />
into two compartments, a medioventral 'shell' <strong>and</strong> a laterodorsal 'core' (see<br />
Figure 1.1.). These NAC subregions have been found to differ anatomically as<br />
well as functionally (Zahm <strong>and</strong> Brog 1992; Cools et al 1993, 1995; Prinssen<br />
et al 1994; Koshikawa et al 1996; Groenewegen et al 1999a, 1999b; Zahm<br />
1999). The later divisions have also been identified in primates (Meredith et al<br />
1996).<br />
Figure 1.1. Dopaminergic<br />
system: The Striatum<br />
(NAC=nucleus accumbens<br />
[core <strong>and</strong> shell]; CPu=caudate<br />
putamen) (Adapted from<br />
Paxinos <strong>and</strong> Watson 1997,<br />
bregma 1.2 mm)<br />
1.1.2. NIGROSTRIATAL SYSTEM<br />
1.1.2.1. Input caudate-putamen<br />
CPu<br />
NAC<br />
core<br />
shell<br />
Cell bodies <strong>of</strong> neurons forming the major ascending dopaminergic (DA)<br />
pathways to the CPu are located in the brainstem, in the retrorubral nucleus<br />
(RRN, A8), the substantia nigra pars compacta (SNc, A9) <strong>and</strong> ventral<br />
tegmental area (VTA, A10) (Björklund <strong>and</strong> Lindvall 1984; Bouyer et al 1984;<br />
Freund et at 1984, Gerfen et al 1987a, Jimenez-Castellanos <strong>and</strong> Graybiel<br />
1987). The CPu is predominantly innervated by the SNc forming the<br />
nigrostriatal DA system (Veening et al 1980; Björklund <strong>and</strong> Lindvall 1984;<br />
Fuxe et al 1985) (see Figure 1.2.). Cortical <strong>and</strong> thalamic fibers provide<br />
excitatory inputs to the CPu (Bouyer et al 1984, Hattori et al 1978, Somogyi<br />
et al 1981) (see Figure 1.3.C.). The DA input to the CPu appears to modulate<br />
the responsiveness <strong>of</strong> striatal output neurons to these cortical <strong>and</strong> thalamic<br />
inputs (for review see Gerfen 1992b).<br />
8
PFC<br />
NAC<br />
3<br />
OT<br />
CC<br />
2<br />
CE<br />
CPu<br />
Figure 1.2. Dopaminergic system:<br />
The Nigrostriatal, Mesolimbic <strong>and</strong> Mesocortical DA pathways<br />
1<br />
ME<br />
ARC<br />
SNc<br />
VTA<br />
RN<br />
1. The SNc neurons project mainly to the caudate-putamen or to the dorsal<br />
striatum forming the nigrostriatal DA system. 2. The mesolimbic DA pathway is<br />
formed by neurons that project from the VTA to the ventral striatum, i.e. the<br />
nucleus accumbens, olfactory tubercle <strong>and</strong> other limbic regions such as the<br />
amygdala 3. The VTA sends axons to the cortical areas, e.g. to the medial<br />
prefrontal cortex <strong>and</strong> cingulate cortex, which system is called the mesocortical<br />
DA pathway. (ARC=arcuate nucleus <strong>of</strong> hypothalamus; CC=cingulate<br />
cortex;CE=central amygdala nucleus; CPu=caudate-putamen; LC=locus<br />
ceruleus; ME=median eminence; NAC=nucleus accumbens; OT=olfactory<br />
tubercle; PFC=prefrontal cortex; RN=raphe nuclei; SNc=substantia nigra pars<br />
compacta; VTA=vental tegmental area) (Adapted from Nehlig 1999)<br />
Specific inputs have been identified for the matrix <strong>and</strong> patch compartments.<br />
Neurons in the VTA, SNc (dorsal tier) <strong>and</strong> the RRN have DA projections that<br />
are directed to the matrix, whereas neurons in the SNc (ventral tier) <strong>and</strong> in<br />
the DA Isl<strong>and</strong>s in the SNr have DA projections to the patches (Gerfen et al<br />
1987b) (see Figure 1.3.A-B.). Furthermore, corticostriatal neurons in the<br />
superficial parts <strong>of</strong> layer 5 <strong>of</strong> the cortex provide inputs to the striatal matrix<br />
compartment, whereas deep layer 5 neurons provide inputs to the striatal<br />
patches (Ferino et al 1987, Wilson 1987).<br />
1.1.2.2. Output caudate-putamen<br />
Projections from GABAergic neurons in the striatum give rise to two<br />
output systems, the direct <strong>and</strong> indirect pathway which have opposite<br />
regulatory roles (Albin et al 1989, Gerfen et al 1990; for review see<br />
Gerfen 1992b) (see Figure 1.3.C.). The indirect pathway is the projection<br />
to the GABAergic external globus pallidus (GPe) neurons that provide<br />
inhibitory inputs to the subthalamic nucleus (STh) <strong>and</strong> to the SN (Smith et<br />
al 1990).<br />
LC<br />
9
VTA, RRN, (dorsal) SNc<br />
Cortex superficial layer 5<br />
(ventral) SNc<br />
(DA cell Isl<strong>and</strong>s) SNr<br />
Cortex deep layer 5<br />
Brainstem:<br />
VTA, RRN,<br />
SNc, SNr<br />
Cortex,<br />
Thalamus<br />
DA<br />
CPu<br />
+<br />
D2<br />
_<br />
+<br />
DA<br />
CPu<br />
matrix<br />
_<br />
_<br />
SNr (GABA)<br />
DA CPu<br />
patches (ventral)<br />
SNc (DA)<br />
GPe<br />
D1<br />
_<br />
+<br />
_<br />
Direct<br />
pathway SNr<br />
(GPi,SNc)<br />
Figure 1.3. Dopaminergic system:<br />
Inputs <strong>and</strong> outputs <strong>of</strong> the dorsal striatum<br />
+<br />
Indirect<br />
pathway<br />
_<br />
STh<br />
SNr (DA cell<br />
Isl<strong>and</strong>s)<br />
VL,<br />
IL<br />
VM,<br />
MD<br />
PPTg<br />
_<br />
A<br />
B<br />
Thalamus<br />
SC<br />
C<br />
CPu<br />
Cortex<br />
CPu<br />
A. Input <strong>and</strong> output CPu matrix neurons B. Input <strong>and</strong> output CPu patch neurons<br />
C. Indirect <strong>and</strong> direct pathway output CPu<br />
(CPu=caudate-putamen; EC=entorhinal cortex; GPe=globus pallidus externa;<br />
GPi=globus pallidus interna; IL=intralaminar thalamic nuclei; MD=mediodorsal<br />
thalamus; PPTg=pendunculopontine tegmental nucleus; RRN= retrorubral<br />
nucleus; SC= superior colliculus; SNc=substantia nigra pars compacta;<br />
SNr=substantia nigra pars reticulata; STh= subthalamic nucleus;<br />
VL=ventrolateral thalamic nuclei; VM=ventromedial thalamic nuclei; VTA=vental<br />
tegmental area. Neurotransmitters: DA=dopamine; -=GABA/γ-Amino-butyric<br />
acid; + =glutamate)<br />
Neurons in the STh provide an excitatory input to the SNr (Kita et al 1983;<br />
Kita <strong>and</strong> Kitai 1987a, 1987b; Nakanishi et at 1988). This indirect pathway is<br />
responsible for the tonic activity <strong>of</strong> GABAergic neurons in the SNr. D2<br />
expressing striatal neurons preferentially project to the GPe (for review<br />
Gerfen 1992b; Fallon <strong>and</strong> Loughlin 1995). The direct striatonigral pathway<br />
provides inhibitory inputs to the DA <strong>and</strong> GABAergic neurons in the SNr, SNc<br />
<strong>and</strong> the internal globus pallidus (GPi) (Chevalier et at 1985, Deniau <strong>and</strong><br />
Chevalier 1985). D1 expressing striatal neurons preferentially project to the<br />
10
GABAergic SNr neurons (for review Gerfen 1992b; Fallon <strong>and</strong> Loughlin 1995).<br />
Subsequently, the GABAergic SNr neurons have inhibitory inputs to the<br />
superior colliculus (SC), the pedunculopontine nucleus (PPTg) <strong>and</strong> the<br />
thalamus (Gerfen 1992b). Nigrothalamic inputs target intralaminar nuclei (IL)<br />
that provide feedback to the striatum. Furthermore, these nigrothalamic<br />
fibers are directed to the ventral <strong>and</strong> mediodorsal thalamic nuclei that provide<br />
inputs to the (pre) motor / (pre) frontal cortex. For instance, the SNr sends<br />
afferents to the ventral lateral nucleus <strong>of</strong> the thalamus (VL) that reaches part<br />
<strong>of</strong> the cortex that innervates the CPu (Aldes 1988), closing the cortico-striatopallido-thalamic<br />
loop (Alex<strong>and</strong>er <strong>and</strong> Crutcher 1990; Gerfen 1992a).<br />
Neurons giving rise to striatopallidal <strong>and</strong> striatonigral projections are<br />
separate <strong>and</strong> intermingled in both striatal patch <strong>and</strong> matrix compartments.<br />
Matrix neurons provide inputs to the location <strong>of</strong> the GABAergic neurons in the<br />
SNr, whereas patch neurons provide inputs to the ventral tier <strong>of</strong> DA neurons<br />
in the SNc <strong>and</strong> DA cell Isl<strong>and</strong>s in the SNr (Gerfen 1984, 1985, Gerfen et al<br />
1985; review Gerfen 1992b) (see Figure 1.3.B-C.).<br />
1.1.2.3. Function nigrostriatal system<br />
Activation <strong>of</strong> nigrostriatal DA transmission by locally applied DA (Jackson et al<br />
1975b), amphetamine or apomorphine (Kelly et al 1975) induce mainly<br />
stereotyped behaviors, e.g. sniffing, grooming, oral movements but not<br />
locomotion. Furthermore, lesioning the nigrostriatal pathway abolishes<br />
amphetamine-induced stereotyped behavior, while it enhances amphetamineinduced<br />
locomotor stimulation. Another role <strong>of</strong> DA in the dorsal striatum is<br />
that it allows subjects to switch ongoing behavior with the help <strong>of</strong> internal<br />
information (Cools et al 1984; Jaspers et al 1984; Oades 1985; Gelissen <strong>and</strong><br />
Cools 1988; Jaspers et al 1990; Arts <strong>and</strong> Cools 1998). Cats with a DA deficit<br />
in the dorsal striatum displayed problems in switching motor programs<br />
without the availability <strong>of</strong> visual <strong>and</strong> tactile information (Jaspers et al 1984).<br />
Finally, it has been suggested that the dorsal striatum contributes to nondrug-induced<br />
conditioned reaction time performance (Amalric <strong>and</strong> Koob 1987;<br />
for review Amalric <strong>and</strong> Koob 1993).<br />
The dorsal striatum is innervated by glutamatergic projections from the<br />
cortical areas <strong>and</strong> therefore it is thought to serve as a modulator <strong>of</strong> cortical<br />
signals (Mogenson 1987). The circuitry as described above (direct <strong>and</strong><br />
indirect pathway) is believed to be central in motor processes (Carlsson <strong>and</strong><br />
Carlsson 1990; Fuxe et al.1985; Gerfen 1992a). Balanced opposition <strong>of</strong> the<br />
direct <strong>and</strong> indirect striatal output systems appears to be responsible for the<br />
generation <strong>of</strong> normal movements. In rest, the GABAergic SNr neurons are<br />
tonically active. In contrast, during the execution <strong>of</strong> movement, activity <strong>of</strong><br />
these GABAergic neurons is decreased through the direct pathway. Increased<br />
activity in the indirect pathway results in increased tonic activity <strong>of</strong> SNr<br />
neurons (Alex<strong>and</strong>er <strong>and</strong> Crutcher 1990) opposing the effect in the direct<br />
pathway.<br />
1.1.3. MESOLIMBIC SYSTEM<br />
1.1.3.1. Input nucleus accumbens<br />
The mesolimbic DA pathway is formed by neurons that project from the VTA<br />
to the ventral striatum (see Figure 1.2.), i.e. the nucleus accumbens (NAC),<br />
olfactory tubercle (OT) <strong>and</strong> other limbic regions such as the amygdala,<br />
hippocampal dendate gyrus (DG) <strong>and</strong> lateral septum (Swanson 1982). The<br />
11
NAC is innervated by glutamatergic fibers from the hippocampal ventral<br />
subicular area (HPC SUB), entorhinal cortex (EC), medial prefrontal cortex<br />
(mPFC), basolateral amygdala (BLA), midline/intralaminar thalamic nuclei<br />
(IL/ML) <strong>and</strong> also receives DA afferents from the VTA <strong>and</strong> SNc (Berendse et al<br />
1992; Groenewegen et al 1987; Heimer et al 1995; Groenewegen et al 1996,<br />
for review Groenewegen et al 1999a, 1999b) (see Figure 1.4.). There are no<br />
afferent systems that exclusively innervate NAC core <strong>and</strong> shell (Groenewegen<br />
1999b). However, the VTA predominantly projects to the medial <strong>and</strong> ventral<br />
parts <strong>of</strong> the shell, but its fibers also terminate in the medial core <strong>and</strong> the CPu,<br />
whereas the SNc projects mainly to the NAC core <strong>and</strong> CPu.<br />
SNc<br />
ML,IL,<br />
BLA,<br />
HPC SUB,<br />
mPFC, EC<br />
VTA<br />
DA<br />
+<br />
DA<br />
NAC core<br />
patches<br />
NAC core<br />
matrix<br />
NAC<br />
shell<br />
_<br />
VTA<br />
SNc<br />
_<br />
_<br />
SNr<br />
_<br />
_<br />
mPFC<br />
SN<br />
DA<br />
Thalamus:<br />
VM,IL,MD<br />
+<br />
Thalamus:<br />
ML,MD,<br />
+<br />
RTN<br />
VP<br />
PPTg<br />
_<br />
DA<br />
CPu<br />
Cortex<br />
Cortex<br />
Figure 1.4. Dopaminergic system: Inputs <strong>and</strong> outputs <strong>of</strong> the ventral striatum<br />
(BLA=basolateral amygdala; CPu=caudate-putamen; EC=entorhinal cortex; HPC<br />
SUB= hippocampal subiculum; IL=intralaminar thalamic nuclei; MD=mediodorsal<br />
thalamus; ML= midline thalamic nuclei; mPFC=medial prefrontal cortex;<br />
NAC=nucleus accumbens; PPTg=pendunculopontine tegmental nucleus;<br />
RTN=reticular thalamic nucleus; SN=substantia nigra; SNc=substantia nigra pars<br />
compacta; SNr=substantia nigra pars reticulata; VM=ventromedial thalamic<br />
nuclei; VP=ventral pallidum; VTA=vental tegmental area. Neurotransmitters:<br />
DA=dopamine; - =GABA/γ-Amino-butyric acid; + =glutamate)<br />
1.1.3.2. Output nucleus accumbens<br />
Ventral striatal outputs reach the SNc, SNr, VTA <strong>and</strong> the ventral pallidum (VP)<br />
(Groenewegen et al 1996, for review Groenewegen et al 1999a, 1999b). The<br />
VP in turn projects to the medial prefrontal cortex (mPFC), thalamus, SN <strong>and</strong><br />
the pedunculopontine tegmental nucleus (PPTg, a part <strong>of</strong> the mesencephalic<br />
locomotor region, Schaefer <strong>and</strong> Michael 1987; for review see Groenewegen et<br />
al 1993) (see Figure 1.4.).<br />
The NAC core patches project to the SNc <strong>and</strong> the NAC core matrix<br />
sends fibers to the (dorsomedial) SNr (Groenewegen et al, 1999b). The NAC<br />
has been shown to inhibit the SNc (Williams et al 1977; Somogyi et al 1981).<br />
Thus, DA activity in the NAC core patches can inhibit the release <strong>of</strong> DA in the<br />
12
dorsal striatum (Kohikawa et al 1996). So, an interaction between the dorsal<br />
<strong>and</strong> ventral striatum takes place via this pathway. The medial NAC shell sends<br />
fibers back to the medial VTA.<br />
Furthermore, Groenewegen et al (1999a) have shown that the shell<br />
<strong>and</strong> core circuits remain largely segregated at the level <strong>of</strong> the thalamus. The<br />
shell projects predominantly to the mediodorsal (MD), midline (ML) <strong>and</strong><br />
reticular (RTN) thalamic nuclei via the VP, whereas the core projects<br />
predominantly to the medial part <strong>of</strong> the ventromedial (VM) thalamic nucleus,<br />
intralaminar (IL) <strong>and</strong> mediodorsal (MD) nuclei via the SNr. However, it has<br />
been proposed that at the level <strong>of</strong> the prelimbic cortex, via the VM <strong>and</strong> MD<br />
nuclei <strong>of</strong> the thalamus, shell <strong>and</strong> core outputs may reach the same cortical<br />
areas (although in different cortical layers) (Groenewegen et al 1999a).<br />
1.1.3.3. Function mesolimbic system<br />
Selective activation <strong>of</strong> the accumbal DA transmission enhances locomotor<br />
activity but does not cause stereotyped behavior (Pijnenburg <strong>and</strong> Van Rossum<br />
1973; Jackson et al 1975a; Kelly et al 1975; Pijnenburg et al 1976). Selective<br />
DA lesions <strong>of</strong> the mesolimbic system abolish amphetamine-induced locomotor<br />
stimulation, while it enhances amphetamine-induced stereotyped behavior<br />
(Kelly et al 1975). DA in the ventral striatum has also been shown to be<br />
involved in the switching <strong>of</strong> ongoing behavior with the help <strong>of</strong> external or cuebound<br />
information (Cools et al 1984; Oades 1985; Van den Bos <strong>and</strong> Cools<br />
1989; Van den Bos et al 1991). Furthermore, the NAC has been proposed to<br />
play a role in the reinforcing properties <strong>of</strong> both drugs <strong>of</strong> abuse <strong>and</strong> <strong>of</strong> natural<br />
rewards such as food (for review Amalric <strong>and</strong> Koob 1993). Rewards increase<br />
DA release in the NAC (Di Chiara <strong>and</strong> Imperato 1988; Kiyatkin 1995) <strong>and</strong><br />
attenuation <strong>of</strong> DA activity in the NAC decreases the reinforcing properties <strong>of</strong><br />
these stimuli (Ettenberg 1989; Wise <strong>and</strong> Bozarth 1987).<br />
Accumbal DA is believed to have a gating function, i.e. it regulates the<br />
information flow from limbic structures such as amygdala <strong>and</strong> HPC to the<br />
motor nuclei (Mogenson 1987). DA-induced hyperactivity is thought to be<br />
caused by its effect on GABAergic neurons projecting to the VP. It has been<br />
suggested that the NAC shell mainly regulates limbic functions, whereas the<br />
core regulates more motor functions (Heimer <strong>and</strong> Alheid 1991; Zahm <strong>and</strong><br />
Brog 1992). Furthermore, specific behaviors have been shown to be<br />
dependent on DA activation in NAC shell or core. Local NAC injections <strong>of</strong> DA<br />
agents only induced jaw movements, oral behavior, pivoting <strong>and</strong> contralateral<br />
turning when injected in the NAC shell (Cools et al 1993, 1995; Prinssen et al<br />
1994; Koshikawa et al 1996; Kitamura et al 1999; Bernstein <strong>and</strong> Beninger<br />
2000). DA in the NAC core <strong>and</strong> shell have been found to have different roles<br />
in motivated behavior (respectively, appetitive food stimuli <strong>and</strong> unpredicted<br />
consumption) (Bassareo <strong>and</strong> Di Chiara 1999). Finally, psychostimulants <strong>and</strong><br />
morphine (when injected IV) have been shown to preferentially increase<br />
extracellular DA in the shell (Pontieri et al 1995).<br />
1.1.4. MESOCORTICAL SYSTEM<br />
The VTA sends axons to cortical areas, e.g. to the medial prefrontal cortex<br />
(mPFC), entorhinal cortex (EC) <strong>and</strong> cingulate cortex (CC). This system is<br />
called the mesocortical DA pathway (Berger et al 1976; Björklund <strong>and</strong><br />
Lindvall 1984; Fuxe et al 1985; Descarries et al 1987) (see Figure 1.2.).<br />
The prefrontal cortex (PFC) is involved in various cognitive processes<br />
such as regulation <strong>of</strong> working memory <strong>and</strong> focused attention <strong>and</strong> these<br />
functions are modulated by the mesocortical DA pathway (Barkley 1998; Le<br />
13
Moal <strong>and</strong> Simon 1991). However, DA in the PFC plays a role in locomotor<br />
activity <strong>and</strong> reinforcement as well. For instance, attenuation <strong>of</strong> DA tone in the<br />
PFC by 6-OHDA lesions increases the stimulatory effects <strong>of</strong> amphetamine<br />
(Carter <strong>and</strong> Pycock 1980). These effects have been suggested to result from<br />
dis<strong>inhibition</strong> <strong>of</strong> the excitatory glutamatergic afferents projecting from the PFC<br />
to the VTA <strong>and</strong> NAC (Taber <strong>and</strong> Fibiger 1995).<br />
1.1.5. DOPAMINE RECEPTORS AND DRUG ACTION<br />
There are at least five DA receptors (D1-D5) <strong>and</strong> these are further divided<br />
into two subfamilies (Sibley <strong>and</strong> Monsma 1992; Civelli et al 1993; Jarvie <strong>and</strong><br />
Caron 1993; Strange 1996). The two subfamilies are termed D1-like (D1, D5)<br />
<strong>and</strong> D2-like (D2, D3, D4). The D1 receptor is expressed in the dorsal <strong>and</strong><br />
ventral striatum, in several limbic regions, hypothalamus <strong>and</strong> thalamus (Jaber<br />
et al 1996). In the striatum, D1 receptors are expressed mainly in the<br />
GABAergic medium-size spiny neurons projecting to the substantia nigra pars<br />
reticulata (SNr). In contrast the D5 receptor is expressed at a lower level <strong>and</strong><br />
its mRNA is detected in the HPC <strong>and</strong> some thalamic nuclei. D2 receptors are<br />
expressed in the dorsal <strong>and</strong> ventral striatum in GABAergic neurons. D3<br />
receptors are mainly in the ventral striatum, i.e. NAC <strong>and</strong> OT. The expression<br />
<strong>of</strong> D3 <strong>and</strong> D4 receptors is low in the dorsal striatum. The expression <strong>of</strong> D4<br />
receptors is high in areas such as the frontal cortex (FC), amygdala <strong>and</strong><br />
hypothalamus (Jaber et al 1996).<br />
Drugs act on these receptors in different ways. Drugs known as DA<br />
agonists bind to DA receptors in place <strong>of</strong> DA <strong>and</strong> directly stimulate these<br />
receptors. In contrast, DA antagonists are drugs that bind but do not<br />
stimulate DA receptors. These drugs can prevent or reverse the actions <strong>of</strong> DA<br />
by keeping DA from attaching to receptors. Indirect acting drugs such as the<br />
DA agonist amphetamine produce their effects by changing the amount <strong>of</strong> DA<br />
release <strong>and</strong> depend on the activity <strong>of</strong> neurons, whereas direct acting drugs<br />
such as the DA agonist apomorphine act directly on postsynaptic receptors.<br />
1.1.6. CONCLUSIONS<br />
The nigrostriatal <strong>and</strong> mesolimbic DA systems differ in input, output <strong>and</strong> in<br />
function. The dorsal striatum (CPu) is predominantly innervated by the cortex<br />
<strong>and</strong> DA fibers from the SNc. The CPu has the SNr as output area. In contrast,<br />
the NAC <strong>of</strong> the ventral striatum is innervated by the cortex, several limbic<br />
structures (such as the HPC, BLA) <strong>and</strong> by the DA fibers from the VTA. The<br />
NAC projects to the VP <strong>and</strong> back to the VTA (via the NAC shell) <strong>and</strong> to the<br />
SNr (via the NAC core matrix). Interactions between both DA systems take<br />
place via the projection from the NAC core patches to the SNc that<br />
subsequently innervates the CPu. Also, the input <strong>and</strong> output <strong>of</strong> the<br />
patch/matrix compartments differ. The VTA mainly innervates the area with<br />
the patch neurons. Patch neurons send fibers to the DA neurons in the SN. In<br />
contrast, matrix neurons provide inputs to the GABAergic neurons in the SN.<br />
A final distinction can be made between the NAC core <strong>and</strong> shell. The NAC core<br />
is predominantly innervated by the SNc <strong>and</strong> has the SNc <strong>and</strong> SNr as output,<br />
whereas the NAC shell mainly receives DA afferents from the VTA <strong>and</strong><br />
projects to the VP <strong>and</strong> back to the VTA.<br />
The dorsal striatum has a role in stereotyped behavior, the execution<br />
<strong>of</strong> learned motor programs <strong>and</strong> the switching <strong>of</strong> ongoing behavior with the<br />
help <strong>of</strong> internal information, whereas the ventral striatum is involved in<br />
locomotor activity, goal-oriented (motivated) behavior, switching <strong>of</strong> ongoing<br />
14
ehavior with the help <strong>of</strong> external/cue-bound information <strong>and</strong> has a role in<br />
reinforcement.<br />
This question remains to be answered<br />
The previous section provides an overview <strong>of</strong> the nigrostriatal <strong>and</strong><br />
mesolimbic DA systems. Several arguments have been presented<br />
that indicate that these systems interact. First, DA activity in the<br />
NAC core patches has been suggested to inhibit the release <strong>of</strong> DA<br />
in the dorsal striatum. Secondly, lesioning the nigrostriatal pathway<br />
abolishes amphetamine-induced stereotyped behavior, while it<br />
enhances amphetamine-induced locomotor stimulation. Third,<br />
selective DA lesions <strong>of</strong> the mesolimbic system abolish<br />
amphetamine-induced locomotor stimulation, while it enhances<br />
amphetamine-induced stereotyped behavior. This suggests that the<br />
action <strong>of</strong> DA in the dorsal striatum is dependent upon the action <strong>of</strong><br />
DA in the ventral striatum <strong>and</strong> vice versa. This poses the question<br />
in what way this balance between both DA systems is involved in<br />
different functions <strong>of</strong> DA in the brain.<br />
1.2. INFORMATION PROCESSING<br />
1.2.1. AUDITORY PATHWAY<br />
Sound is produced by vibrations that result in the alternating compression<br />
<strong>and</strong> rarefaction (increased or decreased pressure) <strong>of</strong> the surrounding air<br />
(Kelley 1991). The frequency (in hertz) <strong>of</strong> the wave/number <strong>of</strong> peaks that<br />
pass a given point per time-unit determines the pitch (highness/lowness) <strong>of</strong> a<br />
sound. The amplitude <strong>of</strong> the wave is the maximum change in air pressure in<br />
either direction <strong>and</strong> this is correlated with the loudness (decibel) <strong>of</strong> a sound.<br />
The ascending <strong>auditory</strong> pathways can be divided into a primary,<br />
lemniscal pathway (1) <strong>and</strong> non-lemniscal pathways (2) (Andersen et al 1980;<br />
see for reviews Weinberger <strong>and</strong> Diamond, 1988; Winer, 1992). Lemniscal<br />
neurons have narrow frequency tuning <strong>and</strong> provide highly specific frequency<br />
information to the <strong>auditory</strong> cortex, whereas non-lemniscal neurons generally<br />
have broader tuning <strong>and</strong> greater response lability (Lennartz <strong>and</strong> Weinberger<br />
1992). Non-lemniscal pathways carry <strong>auditory</strong> information colored by arousal<br />
from the reticular formation (RF) to several brain areas (Harrison et al 1990;<br />
Simpson <strong>and</strong> Knight 1993).<br />
1.2.1.1. Primary lemniscal <strong>auditory</strong> pathway<br />
Sounds that reach the ear set the tympanic membrane in motion <strong>and</strong> this<br />
motion is conducted to the fluid <strong>of</strong> the cochlea by the three ossicles <strong>of</strong> the<br />
middle ear. In turn, motion <strong>of</strong> the fluid in the cochlea sets the basilar<br />
membrane into motion. The sensory cells (hair cells) that are innervated by<br />
the fibers <strong>of</strong> the <strong>auditory</strong> nerve (AN, eight cranial nerve or C.N.VIII) are<br />
located along the basilar membrane <strong>and</strong> convert the motion <strong>of</strong> the basilar<br />
membrane into a neural code. The AN carries the <strong>auditory</strong> information to the<br />
brainstem (see Figure 1.5.). Here, the AN passes through the cochlear nuclei<br />
(CN), which start the neural processing <strong>and</strong> feature extraction process.<br />
15
16<br />
Figure 1.5. Auditory pathway:<br />
Primary lemniscal pathway<br />
(Adapted from<br />
http://www.anatomy.wisc.edu/bs<br />
/text/p12/s/pathway.htm)
Following the CN, the <strong>auditory</strong> pathway is directed to the next processing<br />
center via the trapezoid body, namely the superior olivary nuclei (SO). These<br />
SO receive axons from both the ipsilateral <strong>and</strong> contralateral cochlear nuclei<br />
<strong>and</strong> are suggested to play a role in directional hearing. The medial part <strong>of</strong> the<br />
SO is concerned with measuring interaural time differences while the lateral<br />
part processes interaural intensity information. After leaving the olives, the<br />
axons progress upward via the bundle <strong>of</strong> axons that is called the lateral<br />
lemniscus (LL). The lemniscus ascends first through the pons <strong>and</strong> from there,<br />
the pathway continues upward to the inferior colliculus or IC (midbrain). The<br />
IC is involved in orientation <strong>and</strong> sound-sight coordination. Also, the<br />
topographic organization according to the spatial location <strong>of</strong> the sound is<br />
thought to be located in the IC. The pathway is then extended upward<br />
through the brachium to the medial geniculate body (MGB) (below the<br />
forebrain). The MGB is a set <strong>of</strong> diencephalic nuclei <strong>of</strong> the ventral thalamus<br />
that serves as a relay center for <strong>auditory</strong> inputs to the cortex (see Winer<br />
1985, 1992; Imig <strong>and</strong> Morel 1988 for reviews). The MGB projects to the<br />
primary <strong>auditory</strong> cortex in the temporal lobe (area 41 <strong>and</strong> 42) via the<br />
temporal radiation (Pickles 1981; Jones 1985). The <strong>auditory</strong> cortex is<br />
organized into six neuronal layers (which mainly contain neuronal cell bodies)<br />
<strong>and</strong> into columns (which reach through the layers). The layers show patterns<br />
<strong>of</strong> external connections: layer IV receives the input, layer V projects back<br />
towards the MGB <strong>and</strong> layer VI to the IC. The columns serve more specialized<br />
functions. Finally, the entorhinal cortex (EC) receives input from the primary<br />
<strong>auditory</strong> cortex through pathways synapsing in the association cortex or via<br />
direct projections (Witter et al 1989).<br />
1.2.1.2. Non-lemniscal pathways<br />
Non-lemniscal pathways diverge from the primary <strong>auditory</strong> pathway in the<br />
brainstem. Four brainstem <strong>auditory</strong> relay nuclei (the dorsal <strong>and</strong> ventral<br />
cochlear nuclei [DCN, VCN], the nucleus <strong>of</strong> the LL <strong>and</strong> the IC) sent fibers into<br />
the RF (Powell <strong>and</strong> Hatton 1969; Carpenter 1978; Irvine <strong>and</strong> Jackson 1983)<br />
(see Figure 1.6). RF neurons (including cholinergic neurons <strong>of</strong> the<br />
pedunculopontine tegmental nucleus, PPTg) project via the reticular fasciculus<br />
to the midline <strong>and</strong> intralaminar nuclei <strong>of</strong> the thalamus (e.g. the centromedial<br />
nuclei) that subsequently project diffusely to most areas <strong>of</strong> the cortex (Jones<br />
1985; Woolf et al 1990; Harrison et al 1990; Berendse <strong>and</strong> Groenewegen<br />
1991; Newman <strong>and</strong> Ginsberg 1994; Groenewegen <strong>and</strong> Berendse 1994). The<br />
centromedial thalamic nucleus has been found to directly project to the EC<br />
(Witter et al 1989). In addition, the noradrenergic locus coeruleus (LC) <strong>and</strong><br />
the serotonergic raphe nuclei (RN) <strong>of</strong> the RF project directly <strong>and</strong> diffusely to<br />
the cortex (Cooper et al 1991). The EC receives these RF projections, as well<br />
as receiving indirect RF influences via multisynaptic thalamocortical <strong>and</strong><br />
corticocortical connections (Harrison et al 1990; Witter et al 1989).<br />
Thalamus: ML/IL<br />
(e.g. CM)<br />
RF e.g. PPTg<br />
DCN VCN<br />
LL IC<br />
Cortex (e.g. EC)<br />
ACH<br />
NE 5-HT<br />
LC RN<br />
Figure 1.6. Auditory pathway:<br />
Non-lemniscal pathway<br />
(CM=centromedial nuclei; DCN=dorsal<br />
cochlear nuclei; EC=entorhinal cortex;<br />
IC=inferior colliculus; IL=intralaminar<br />
nuclei; LC=locus ceruleus; LL=lateral<br />
lemniscus; ML=midline nuclei; RF=reticular<br />
formation; RN=raphe nuclei; VCN=ventral<br />
cochlear nuclei; Neurotransmitters:<br />
ACH=acetylcholine; NE=noradrenaline;<br />
5-HT=5-Hydroxytryptamine [serotonin])<br />
17
1.2.2. PREPULSE INHIBITION OF THE ACOUSTIC STARTLE RESPONSE<br />
1.2.2.1. Acoustic startle response (ASR)<br />
The acoustic startle response (ASR) is a short latency motor response<br />
common in most species (e.g. humans, rats <strong>and</strong> mice) following an<br />
unexpected <strong>and</strong> intense acoustic stimulus, probably serving a protective<br />
function. In humans, changes in electrical activity in neck muscles can occur<br />
within 9 ms after the onset <strong>of</strong> an <strong>auditory</strong> stimulus <strong>and</strong> within 14 ms in jaw<br />
muscles (Davis et al 1982). In rats, startle occurs within 5 ms in the neck <strong>and</strong><br />
8 ms in the hindlegs. Davis et al (1982) have described the circuitry involved<br />
in the ASR after lesioning <strong>and</strong> electrically stimulating different structures (see<br />
Figure 1.7.). According to these authors, the primary acoustic startle pathway<br />
consists <strong>of</strong> three synapses onto cochlear root neurons (1), neurons in the<br />
nucleus reticularis pontis caudalis or PnC (2) <strong>and</strong> motor neurons (3) in the<br />
facial motor nucleus (pinna reflex) or spinal cord (whole body startle). The<br />
PnC can be considered as the interface between the sensory (from cochlear<br />
nuclei to reticular formation) <strong>and</strong> motor circuit (in the reticular formation <strong>and</strong><br />
spinal cord).<br />
18<br />
cochlear<br />
root<br />
neurons<br />
motor neurons<br />
Caudal pontine<br />
reticular<br />
nucleus (PnC)<br />
Figure 1.7. Prepulse <strong>inhibition</strong>:<br />
Primary acoustic startle circuitry<br />
(Adapted Davis et al 1982)
1.2.2.2. Prepulse <strong>inhibition</strong> (PPI) in human subjects<br />
In humans, the ASR is usually measured with the eye-blink reflex using<br />
electromyography or EMG <strong>of</strong> the orbicularis oculi muscle. The ASR can either<br />
be enhanced or inhibited depending on the particular experimental<br />
manipulation (see for reviews Koch <strong>and</strong> Schnitzler 1997; Koch 1999).<br />
Prepulse <strong>inhibition</strong> (PPI, also sensorimotor gating) is the reduction in the ASR<br />
that occurs when a weak stimulus (<strong>prepulse</strong>) precedes a startling stimulus<br />
with interstimulus intervals between 30 <strong>and</strong> 500 ms (see Figure 1.8.).<br />
Typically, 50-80% response <strong>inhibition</strong> has been reported. Besides acoustic<br />
<strong>prepulse</strong>s, also tactile <strong>and</strong> visual <strong>prepulse</strong>s can be used to inhibit the ASR<br />
(Blumenthal <strong>and</strong> Gescheider 1987; Campeau <strong>and</strong> Davis 1995).<br />
PPI is increased with increasing <strong>prepulse</strong> intensity (Blumenthal 1995).<br />
The optimal interstimulus interval (ISI) between the <strong>prepulse</strong> <strong>and</strong> the startle<br />
stimulus is 120 ms in humans (Graham <strong>and</strong> Murray 1977) <strong>and</strong> PPI fades<br />
gradually till it is absent at 500 ms (H<strong>of</strong>fman <strong>and</strong> Searle 1968). Inhibition is<br />
not affected when paired <strong>prepulse</strong>s are presented instead <strong>of</strong> a single pulse<br />
(Blumenthal 1995). PPI shows high test-retest reliability in humans<br />
(Schwarzkopf et al 1993). However, PPI has been shown to be enhanced if a<br />
subject attends to a <strong>prepulse</strong> (Ison <strong>and</strong> Ashkenazi 1980; Filion et al 1993;<br />
Blumenthal <strong>and</strong> Flaten 1994; Jennings et al 1996). In this respect, Koch<br />
(1999) concluded that attentional mechanisms affect PPI at the perceptual<br />
level, whereas higher levels <strong>of</strong> stimulus processing (cognitive processes) are<br />
protected by the gating mechanism. It has been argued by Swerdlow et al<br />
(2000) that such effects <strong>of</strong> attentional mechanisms on PPI only occur with<br />
longer ISIs (>120 ms) between the <strong>prepulse</strong> <strong>and</strong> startle (see also Filion et al<br />
1998). Besides decreasing the ASR, a <strong>prepulse</strong> has also been found to<br />
potentiate ASR. This phenomenon <strong>of</strong> <strong>prepulse</strong> facilitation (PPF) is still very<br />
elusive. It is not clear whether <strong>inhibition</strong> <strong>and</strong> facilitation can be considered as<br />
two sides <strong>of</strong> one continuum or two completely different <strong>and</strong> independent<br />
processes. Ison et al (1990) have proposed that stimulus anticipation focuses<br />
excitatory <strong>and</strong> inhibitory processes simultaneously on different ASR pathways<br />
in human subjects: <strong>inhibition</strong> central <strong>and</strong> excitation peripheral. Reijmers <strong>and</strong><br />
Peeters (1994b) have also suggested that PPI <strong>and</strong> PPF are not mediated by<br />
the same neural system.<br />
Figure 1.8.<br />
Prepulse <strong>inhibition</strong>: Paradigm<br />
Trial 1: With a startle pulse<br />
alone, a large ASR is found<br />
Trial 2: When a <strong>prepulse</strong><br />
precedes the startle pulse,<br />
the ASR is inhibited<br />
(Adapted from Swerdlow <strong>and</strong><br />
Geyer 1998)<br />
PPI is disturbed in schizophrenic patients (Braff et al 1978, 1992). The<br />
facilitation <strong>of</strong> the ASR latency that normally occurs with a <strong>prepulse</strong> was still<br />
intact in patients. Therefore, it has been suggested by Braff et al (1992b) that<br />
the PPI deficit in patients is not due to a failure in stimulus detection <strong>and</strong> that<br />
the deficit is centrally mediated. Subjects with schizotypal personality<br />
disorder <strong>and</strong> asymptomatic first-degree relatives <strong>of</strong> schizophrenic patients<br />
19
have deficits in PPI as well, which has been suggested to support the<br />
importance <strong>of</strong> PPI as a biological marker for schizophrenia spectrum disorders<br />
(Cadenhead et al 1993, 1999).<br />
Besides in schizophrenic patients, PPI deficits have also been reported<br />
in obsessive-compulsive disorder patients (Swerdlow et al 1993). Corticostriato-pallido-pontine<br />
circuitry dysfunctions have been implicated in PPI<br />
deficits, as will be discussed later. Thus, it can be expected that certain<br />
patients with disorders in this brain circuitry would also show a PPI decrease<br />
compared to healthy subjects. Indeed, Swerdlow et al (1995) have also found<br />
a PPI disruption in patients with Huntington's disease <strong>and</strong> they identify the<br />
striatum <strong>and</strong> striatopallidal GABAergic efferent circuitry as critical substrates<br />
for the PPI decrease. Furthermore, it has also been shown that subjects<br />
comorbid for attention-deficit hyperactivity disorder (ADHD) <strong>and</strong> a tic disorder<br />
(Tourette's syndrome) have significantly reduced PPI, compared to controls<br />
<strong>and</strong> subjects with ADHD alone (Castellanos et al 1996). The authors have<br />
suggested that deficient pallidal <strong>inhibition</strong> plays a role in this PPI reduction.<br />
A significant correlation between deficits in PPI <strong>and</strong> thought disorder<br />
(Roschach-derived thought disturbance measures) have been reported<br />
recently within groups <strong>of</strong> schizophrenic patients (Perry <strong>and</strong> Braff 1994; Perry<br />
et al 1999).<br />
Thought disorder refers to problems in the way that a person with<br />
schizophrenia processes <strong>and</strong> organizes thoughts. For example, the person<br />
may be unable to connect thoughts into logical sequences. Racing thoughts<br />
come <strong>and</strong> go so rapidly that it is not possible to catch them. Because<br />
thinking is disorganized <strong>and</strong> fragmented, the ill persons' speech is <strong>of</strong>ten<br />
incoherent <strong>and</strong> illogical. Thought disorder is frequently accompanied by<br />
inappropriate emotional responses: words <strong>and</strong> mood do not appear in tune<br />
with each other. The result may be something like laughing when speaking<br />
<strong>of</strong> somber or frightening events.<br />
George: "I can remember having thought patterns when I was really sick<br />
where it seemed like listening to 10 different radio stations that weren't<br />
quite on the station. I would get jumbled up little bits <strong>of</strong> each one <strong>of</strong> them<br />
<strong>and</strong> it was all disjointed <strong>and</strong> it didn't make any sense. It was hard to<br />
concentrate <strong>and</strong> figure out the simplest things like what to have for<br />
breakfast or how to get to work." (Schizophrenia: A H<strong>and</strong>book for Families)<br />
Also, correlations between PPI deficits <strong>and</strong> psychotic symptoms (Braff et al<br />
1999; Weike et al 2000) <strong>and</strong> distractibility (Karper et al 1996) were found in<br />
patients. Patients receiving typical antipsychotics showed less PPI with 30 ms<br />
<strong>and</strong> 60 ms <strong>prepulse</strong> trials than control subjects (Kumari et al 1999).<br />
Interestingly, a normalization <strong>of</strong> PPI was observed by the atypical<br />
antipsychotic clozapine (Kumari et al 1999).<br />
1.2.2.3. PPI in rats<br />
The ASR in rats is <strong>of</strong>ten assessed by means <strong>of</strong> the whole body response (see<br />
Figure 1.9. for the startle box). PPI is maximal at an interstimulus interval<br />
(ISI) <strong>of</strong> 100 ms (Ison et al 1973) <strong>and</strong> at <strong>prepulse</strong> durations <strong>of</strong> 10-20 ms<br />
(Reijmers <strong>and</strong> Peeters 1994b). PPI is decreased with a 500 ms ISI between<br />
the startle pulse <strong>and</strong> <strong>prepulse</strong> as compared to an ISI <strong>of</strong> 100 ms (Ellenbroek et<br />
al 1999). Reijmers <strong>and</strong> Peeters (1994b) have observed PPF with larger ISIs<br />
(>800 ms). Furthermore, PPI increases with increasing <strong>prepulse</strong> intensity<br />
(Reijmers <strong>and</strong> Peeters 1994b). PPI is thought to be a pre-attentional process<br />
20
as it appears on the initial pairing <strong>of</strong> the <strong>prepulse</strong> <strong>and</strong> the pulse (Wu et al<br />
1984). This also suggests that PPI is not learned (Swerdlow et al 2000). This<br />
does not preclude the possibility that attentional processes (Filion et al 1998;<br />
Koch 1999) might modulate PPI. PPI in rats has been shown to decline across<br />
trials if <strong>prepulse</strong>s are close to detection threshold. Gewirtz <strong>and</strong> Davis (1995)<br />
have proposed that this could be due to a reduction in <strong>prepulse</strong> detection due<br />
to a decrease in attention across trials. However, it is still illusive whether<br />
such effects are due to attentional processes or changes in generalized<br />
arousal (Filion et al 1998). Experience with or prior exposure to startling<br />
stimuli has been shown to enhance the inhibitory effects <strong>of</strong> visual <strong>and</strong><br />
acoustic <strong>prepulse</strong>s (Ison et al 1973). These authors have suggested that this<br />
effect could reflect an increase in a non-specific state <strong>of</strong> alertness or arousal.<br />
Figure 1.9.<br />
Prepulse <strong>inhibition</strong>:<br />
Startle reactivity box<br />
(San Diego Instruments)<br />
1.2.2.4. Neural substrate <strong>of</strong> PPI<br />
The neural substrate implicated in PPI is referred to as the cortico-striatopallido-pontine<br />
circuitry (see Figure 1.10.) (For reviews: Swerdlow et al<br />
1992a; Swerdlow 1996; Koch <strong>and</strong> Schnitzler 1997; Swerdlow <strong>and</strong> Geyer<br />
1998; Koch 1999; Swerdlow et al 2000). The pendunculopontine nucleus <strong>of</strong><br />
the tegmentum (PPTg) directly innervates the caudal pontine reticular nucleus<br />
(PnC) that has been found to be responsible for the elicitation <strong>of</strong> the ASR<br />
(Davis et al 1982). Electrolytic or quinolinic acid lesions <strong>of</strong> the PPTg <strong>and</strong><br />
infusion <strong>of</strong> the GABA-A agonist muscimol into the PPTg eliminate PPI in rats<br />
(Swerdlow <strong>and</strong> Geyer 1993b; Kodsi <strong>and</strong> Swerdlow 1997). In turn, the PPTg is<br />
innervated by the ventral pallidum (VP) via a GABAergic mechanism <strong>and</strong> by<br />
the superior colliculus (SC, receives inputs from different sensory modalities).<br />
Lesioning <strong>of</strong> the inferior colliculus (IC), a structure that innervates the SC,<br />
has also been shown to disrupt PPI (Leitner <strong>and</strong> Cohen 1985). Lesions <strong>of</strong> the<br />
basolateral amygdala (BLA) reduce PPI (Decker et al 1995; Wan <strong>and</strong><br />
Swerdlow 1997) via the projection to the VP (Wan <strong>and</strong> Swerdlow 1997).<br />
Several glutamatergic fibers from the hippocampus (HPC), medial prefrontal<br />
cortex (mPFC), amygdala <strong>and</strong> cingulate gyrus <strong>and</strong> DA fibers from the VTA all<br />
converge on the nucleus accumbens (NAC). A reduction in PPI is observed<br />
after quinolinic acid lesions <strong>of</strong> this center <strong>of</strong> convergence (Kodsi <strong>and</strong> Swerdlow<br />
1994). Experimental manipulation <strong>of</strong> structures projecting to the NAC such as<br />
the mPFC <strong>and</strong> HPC have also been found to affect PPI. Ibotenic acid lesions <strong>of</strong><br />
the HPC in adult rats result in the development <strong>of</strong> supersensitivity to the PPIdisruptive<br />
effects <strong>of</strong> the DA agonist apomorphine (Swerdlow et al 1995b). The<br />
ventral HPC is innervated by the medial septum. Stimulation <strong>of</strong> the medial<br />
septum by injection <strong>of</strong> the glutamate agonist kainate led to a pr<strong>of</strong>ound<br />
disturbance <strong>of</strong> PPI <strong>and</strong> reduced the ASR amplitude, an effect that could be<br />
attenuated by systemic or intrahippocampal administration <strong>of</strong> the<br />
21
acetylcholine antagonist scopolamine (Koch 1996). However, lesions <strong>of</strong> the<br />
medial septum, made by the neurotoxin AMPA, did not affect PPI (Koch<br />
1996). In sum, these findings indicate that activation <strong>of</strong> the<br />
septohippocampal system reduces PPI. The role <strong>of</strong> the dorsal striatum<br />
(caudate-putamen or CPu) has not been investigated as extensive as the role<br />
<strong>of</strong> the ventral striatum (NAC). The reduction in DA in the dorsal striatum in<br />
both lesioned rats <strong>and</strong> Parkinson patients results in increased sensitivity to<br />
the PPI-disruptive effects <strong>of</strong> the DA agonist apomorphine (respectively,<br />
Swerdlow et al 1986 <strong>and</strong> Morton et al 1995). Furthermore, a lesion study<br />
(Kodsi <strong>and</strong> Swerdlow 1995) showed that the caudodorsal <strong>and</strong> not the<br />
rostrodorsal or middorsal striatum is involved in PPI. They have suggested<br />
that the caudodorsal striatum mediates PPI via the GABAergic pathway to the<br />
caudal dorsal pallidum that innervates the PPTg. Blockade <strong>of</strong> neuronal<br />
transmission by tetratoxin (TTX) within the medial geniculate body (MGB) <strong>of</strong><br />
the thalamus has been found to reduce PPI (Zhang et al 1999). The authors<br />
propose that <strong>auditory</strong> signals relayed through the MGB might activate<br />
feedback <strong>inhibition</strong> <strong>of</strong> subsequent signals involving GABA receptors. Finally,<br />
lesioning <strong>of</strong> the mPFC has been found to increase the sensitivity to the<br />
apomorphine-induced disruption <strong>of</strong> PPI (Swerdlow et al 1995a). Recently, also<br />
attenuation in PPI has been reported following cytotoxic lesions <strong>of</strong> the mPFC<br />
(Yee 2000). It has been suggested that reduced mPFC function could disrupt<br />
PPI via dis<strong>inhibition</strong> <strong>of</strong> descending glutamatergic fibers, which results in<br />
subcortical increases in DA transmission in the NAC. This assumption has<br />
been corroborated by the finding that local injections <strong>of</strong> the GABA-A channel<br />
blocker picrotoxin into the mPFC has been found to reduce PPI, an effect that<br />
could be prevented by systemic pretreatment with the DA antagonist<br />
haloperidol (Japha <strong>and</strong> Koch 1999). These data also suggest a role for mPFC<br />
GABA receptors in these PPI disruptive effects.<br />
S<br />
IC<br />
22<br />
mPFC<br />
BLA<br />
RN<br />
+<br />
5-HT<br />
SC<br />
cochlear root<br />
neurons<br />
VTA<br />
DA<br />
vHPC<br />
+<br />
ACH<br />
DA<br />
+<br />
+<br />
VP<br />
PPTg<br />
+<br />
_ _<br />
+<br />
_<br />
PnC<br />
NAC<br />
ACH<br />
+<br />
CDS<br />
_<br />
_ CDP<br />
motor<br />
neurons<br />
mSEPTUM<br />
dHPC<br />
ASR<br />
Figure 1.10. Prepulse <strong>inhibition</strong>:<br />
Circuitry<br />
(BLA=basolateral amygdala;<br />
CDP=caudodorsal pallidum;<br />
CDS=caudodorsal striatum;<br />
dHPC=dorsal hippocampus;<br />
IC=inferior colliculus; NAC=nucleus<br />
accumbens; mPFC=medial prefrontal<br />
cortex; mSEPTUM=medial septum;<br />
PPTg=pendunculopontine tegmental<br />
nucleus; PnC= caudal pontine<br />
reticular nucleus; RN=raphe nuclei;<br />
SC=superior colliculus; vHPC=ventral<br />
hippocampus; VP=ventral pallidum;<br />
VTA=vental tegmental area.<br />
Neurotransmitters:<br />
CH=acetylcholine; DA=dopamine;<br />
- =γ-Amino-butyric acid;<br />
+ =glutamate; 5-HT=5-Hydroxytryptamine<br />
[serotonin])<br />
(Adapted from Koch 1999)
1.2.2.5. Pharmacology <strong>of</strong> PPI<br />
1. Dopamine Effects <strong>of</strong> dopamine on PPI are presented in Table 1.1. Swerdlow<br />
et al (2000) have concluded that the largest degree <strong>of</strong> cross-species<br />
homology in the neural regulation <strong>of</strong> PPI is found in the DA system. DA<br />
agonists have been found to reduce PPI in both human subjects <strong>and</strong> in rats<br />
(Mansbach et al 1988; Swerdlow et al 1990, 1992a, 1996; Rigdon et al 1990;<br />
Young et al 1991; Campeau <strong>and</strong> Davis 1995; Ott <strong>and</strong> M<strong>and</strong>el 1995; Hutchison<br />
<strong>and</strong> Swift 1999; Abduljawad et al 1999; Sills 1999; Wadenberg et al 2000).<br />
This effect has been linked to a hyperactivity <strong>of</strong> DA at NAC D2 receptors<br />
(Swerdlow et al 1991; Wan <strong>and</strong> Swerdlow 1993; Wan et al 1994; Caine et al<br />
1995, Varty <strong>and</strong> Higgens 1998; Ralph et al 1999) <strong>and</strong> has been shown to be<br />
only slightly NAC core/shell site-specific with a small predominance <strong>of</strong> core D2<br />
effects (Wan et al 1994). Zhang et al (2000) have found an increase in DA<br />
overflow in the NAC (using microdialysis) following administration <strong>of</strong><br />
amphetamine (SC) that showed a reverse relationship over time with the<br />
amount <strong>of</strong> PPI. Furthermore, it has been suggested that D1 <strong>and</strong> D2 receptors<br />
may interact in the regulation <strong>of</strong> PPI (Peng et al 1990; Schwarzkopf et al<br />
1993; H<strong>of</strong>fman <strong>and</strong> Donovan 1994; Wan et al 1996b). DA infusion in the<br />
anteromedial <strong>and</strong> not the posterolateral striatum has been found to disrupt<br />
PPI (Swerdlow et al 1992). Finally, a decrease in PFC DA activity also<br />
decreases PPI. This has been shown by depleting medial PFC DA by infusion<br />
<strong>of</strong> 6-hydroxydopamine (6-OHDA) (Bubser <strong>and</strong> Koch 1994; Koch <strong>and</strong> Bubser<br />
1994) <strong>and</strong> by infusion <strong>of</strong> D1 <strong>and</strong> D2 antagonists (respectively, SCH 23390<br />
<strong>and</strong> sulpiride) in the medial PFC <strong>and</strong> orbital PFC (Ellenbroek et al 1995;<br />
Zavitsanou et al 1999). These effects have been suggested to result from<br />
dis<strong>inhibition</strong> <strong>of</strong> the excitatory glutamatergic afferents projecting from the PFC<br />
to the VTA <strong>and</strong> NAC, which results in subcortical increases in DA transmission<br />
in the NAC.<br />
2. Other neurotransmitters Many researchers have found a PPI reduction<br />
following systemic injections <strong>of</strong> non-competitive (N-methyl-D-aspartate)<br />
NMDA receptor antagonists that are known to reduce the glutamate activity in<br />
the brain (Geyer et al 1989; Mansbach 1991; Mansbach <strong>and</strong> Geyer 1991;<br />
H<strong>of</strong>fman et al 1993; Bakshi et al 1994; Johansson et al 1994; Wiley 1994;<br />
Reijmers et al 1995). Local effects in the NAC or ventral subiculum (vSUB) do<br />
not mediate the systemic effects, since the effects are opposite. First, PPI is<br />
disrupted by intra-NAC infusion <strong>of</strong> glutamate (Swerdlow et al 1992b) or<br />
glutamate agonists such as NMDA (Reijmers et al 1995; Wan et al 1995b)<br />
<strong>and</strong> AMPA (Wan et al 1995a). Secondly, PPI is also disrupted by NMDA<br />
infusion into the vSUB <strong>and</strong> this effect is reversed by coinfusion <strong>of</strong> the NMDA<br />
antagonist D,L-amino-5-phosphono-valeric acid (APV) (Wan et al 1996a).<br />
Also, no change in PPI was produced by the NMDA antagonist dizocilpine into<br />
the NAC, ventral hippocampus, or dorsomedial thalamus. In contrast,<br />
dizocilpine significantly decreased PPI after infusion into the amygdala or<br />
dorsal hippocampus <strong>and</strong> a trend toward PPI disruption was observed with<br />
administration into the mPFC (Bakshi <strong>and</strong> Geyer 1998). In short, local effects<br />
in the amygdala or dorsal hippocampus probably mediate systemic effects <strong>of</strong><br />
non-competitive NMDA antagonists.<br />
23
Table 1.1. Dopaminergic effects on PPI<br />
Species area PPI↓ Reversal reference<br />
DA<br />
Rat ⎯ apomorphine (D1/2 ag)<br />
amphetamine (DA ag)<br />
haloperidol (DA anta) Mansbach et al '88<br />
Rat ⎯ amphetamine (DA ag) DA lesion (6-OHDA) Swerdlow et al '90<br />
Rat ⎯ apomorphine (D1/2 ag) Rigdon et al '90<br />
Rat ⎯ apomorphine (D1/2-ag) Young et al '91<br />
Rat ⎯ apomorphine (D1/2 ag)<br />
<strong>auditory</strong> <strong>and</strong> visual PP<br />
Campeau <strong>and</strong><br />
Davis '95<br />
Rat ⎯ amphetamine (DA ag) Ott <strong>and</strong> M<strong>and</strong>el '95<br />
Rat ⎯ apomorphine (D1/2 ag)<br />
haloperidol (DA anta)<br />
risperidon (D2/5-HT2<br />
anta)<br />
Rat ⎯ amphetamine (DA ag) Sills '99<br />
Swerdlow et al '96<br />
Human ⎯ amphetamine (DA ag) Hutchison <strong>and</strong><br />
Swift '99<br />
Human ⎯ bromocriptine (D2 ag) haloperidol (DA anta) Abduljawad et al<br />
'99<br />
Rat ⎯ amphetamine (DA ag) Zhang et al 2000<br />
Rat ⎯ apomorphine (D1/2 ag)<br />
DA RECEPTOR<br />
SUBTYPES<br />
Rat ⎯ quinpirole (D2/D3 ag)<br />
SKF 38392 (D1 ag)<br />
subthreshold<br />
combination<br />
amoxapine (D2/5-HT2<br />
anta)<br />
Rat ⎯ apomorphine (DA ag) raclopride (D2 anta)<br />
spiperone (D2 anta)<br />
SCH 23390 (D1 anta)<br />
clozapine (low dose)<br />
clozapine (high<br />
dose)<br />
Rat ⎯ apomorphine (DA ag) haloperidol (D2 anta)<br />
SCH 23390 (D1 anta)<br />
combination:<br />
potentiation<br />
Rat ⎯ apomorphine (DA ag) eticlopride (D2 anta)<br />
SCH 23390 (D1 anta)<br />
Rat ⎯ quinpirole (D2/3 ag)<br />
7-OH-DPAT (D2/3 ag)<br />
apomorphine (D1/2 ag)<br />
Rat ⎯ (+)-PF 128907 (D3 ag)<br />
Rat ⎯ Subthreshold<br />
combination <strong>of</strong><br />
quinpirole (D2/D3 ag)<br />
<strong>and</strong> SKF 38392 (D1 ag)<br />
24<br />
SKF 82958 (D1 ag)<br />
haloperidol (DA anta)<br />
UH 232 (DA anta)<br />
equal D3 affinity,<br />
haloperidol (>D2 aff)<br />
raclopride (D2 anta)<br />
SCH 23390 (D1 anta)<br />
Wadenberg et al<br />
2000<br />
Peng et al '90<br />
Swerdlow et al '91<br />
Schwarzkopf et al<br />
'93<br />
H<strong>of</strong>fman <strong>and</strong><br />
Donovan '94<br />
Caine et al '95<br />
Bristow et al '96<br />
Wan et al '96
Species area PPI↓ Reversal reference<br />
Rat ⎯ quinpirole (D2/3 ag)<br />
7-OH-DPAT (D2/3 ag)<br />
PD 128907 (D2/D3 ag)<br />
quinpirole (D2/3 ag)<br />
apomorphine (D1/2 ag)<br />
bromocriptine (D2<br />
ag)<br />
SKF 38393 (D1/5 ag)<br />
cocaine (DA ↑)<br />
GBR 12909 (DA ↑)<br />
Knock-out<br />
mice<br />
⎯ amphetamine (DA ag)<br />
D2 (-/-) D2 (+/+)<br />
D3 (-/-) D3 (+/+)<br />
D4 (-/-) D4 (+/+)<br />
raclopride (D2/3 anta)<br />
WAY 100135 (5-<br />
HT1A anta)<br />
domperidone (D2<br />
anta periphery)<br />
Varty <strong>and</strong><br />
Higgens'98<br />
Ralph et al '99<br />
Rat ⎯ 7-OH-DPAT (D2/3 ag) Ellenbroek et al '99<br />
CLOZAPINE AND D4<br />
Rat ⎯ apomorphine (DA ag)<br />
Rat ⎯ amphetamine (DA ag)<br />
clozapine<br />
seroquel (D2/5-HT2<br />
anta)<br />
clozapine<br />
NRA 0045 (D4 anta)<br />
haloperidol<br />
Rat ⎯ apomorphine (DA ag) clozapine<br />
CP-293,019 (D4 anta)<br />
U-101,387 (D4 anta)<br />
L-745,870 (D4 anta)<br />
Swerdlow et al '94<br />
Okuyama et al '97<br />
Mansbach et al '98<br />
Rat ⎯ apomorphine (DA ag) clozapine Okuyama et al '99<br />
LOCAL EFFECTS<br />
Rat VMT apomorphine (DA ag) Young et al '95<br />
Rat mPFC DA lesion (6-OHDA) Bubser <strong>and</strong><br />
Koch'94<br />
Rat mPFC DA lesion (6-OHDA) haloperidol (DA anta) Koch <strong>and</strong><br />
Bubser'94<br />
Rat mPFC SCH 39166 (D1-anta)<br />
sulpiride (D2-anta)<br />
Rat ORB PFC SCH 39166 (D1-anta)<br />
sulpiride (D2-anta)<br />
Rat NAC<br />
AMS<br />
amygdala<br />
ORB PFC<br />
PLS<br />
Ellenbroek et al '96<br />
Zavitsanou et al<br />
'99<br />
DA Swerdlow et al '92<br />
Rat NAC DA Swerdlow et al '90<br />
Rat NAC quinpirole (D2 ag) haloperidol Wan <strong>and</strong> Swerdlow<br />
'93<br />
Rat NAC quinpirole Wan et al '94<br />
6-OHDA EFFECTS<br />
Rat ⎯ apomorphine (DA ag):<br />
lesioned > sham<br />
Effects are not significant when printed in bold-italic<br />
Schwarzkopf et al<br />
'92<br />
(ag=agonist; AMS=anteromedial striatum; anta=antagonist; DA=dopamine;<br />
mPFC=medial prefrontal cortex; NAC=nucleus accumbens; ORB PFC=orbital<br />
prefrontal cortex; PLS=posterolateral striatum; VMT=ventromedial thalamus)<br />
25
Besides dopamine <strong>and</strong> glutamate also the serotonergic <strong>and</strong> cholinergic<br />
systems have been implicated in PPI deficits. PPI reduction has been<br />
observed after stimulation <strong>of</strong> 5-HT1 <strong>and</strong> 5-HT2 receptors (Rigdon <strong>and</strong><br />
Weatherspoon 1992; Sipes <strong>and</strong> Geyer 1994, 1997) in rats. Smoking in<br />
deprived healthy smokers has been found to enhance PPI for a short period <strong>of</strong><br />
time (Kumari et al 1996), whereas smoking withdrawal after nicotine<br />
dependence decreased PPI in healthy subjects (Kumari <strong>and</strong> Gray 1999).<br />
Finally, several researchers have shown that the muscarinic acetylcholine<br />
antagonist scopolamine can decrease PPI (Wu et al 1993; Fendt <strong>and</strong> Koch<br />
1999; Jones <strong>and</strong> Shannon 2000).<br />
3. Non-pharmacological manipulations: Neurodevelopmental animal models<br />
for schizophrenia such as isolation rearing <strong>and</strong> maternal deprivation have also<br />
been shown to reduce PPI (Wilkinson et al 1994; Bristow et al 1995; Varty<br />
<strong>and</strong> Higgens 1995; Bakshi et al 1998; Ellenbroek et al 1998; Varty <strong>and</strong> Geyer<br />
1998; Varty et al 1999a; 1999b). Finally, differences between rat <strong>and</strong> mice<br />
strains in PPI <strong>and</strong> drug-induced changes in PPI have been found (Rigdon<br />
1990; Ellenbroek et al 1995; Logue et al 1997; Paylor <strong>and</strong> Crawley 1997;<br />
Swerdlow 1998).<br />
1.2.3. P50 GATING PARADIGM<br />
1.2.3.1. EEG <strong>and</strong> <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong> (AEPs)<br />
The human brain produces electrical activity associated with currents<br />
generated across neuronal membranes. Some <strong>of</strong> this electrical activity is<br />
conducted to the scalp. An electroencephalogram (EEG) is a recording <strong>of</strong> this<br />
electrical activity obtained from electrodes placed on the scalp (Duffy et al<br />
1989).<br />
Stimulation <strong>of</strong> sensory receptors can produce waves <strong>of</strong> positive <strong>and</strong><br />
negative deflections in the EEG, called <strong>evoked</strong> <strong>potentials</strong> (EPs). EPs are waves<br />
in the EEG that result from a sensory event such as a light or a click. Most<br />
EPs cannot be clearly seen on an EEG record, because they are generally <strong>of</strong><br />
low amplitude relative to the normal background brain wave activity. Thus, it<br />
is necessary to average the electrical activity over multiple presentations <strong>of</strong><br />
the same stimulus. Since the background EEG activity will be r<strong>and</strong>om relative<br />
to the sensory event, the EP will be seen clearly after averaging <strong>of</strong> a few trials<br />
(Kolb <strong>and</strong> Whishaw 1990). Particular EP deflections are usually referred to in<br />
terms <strong>of</strong> their latency, or how long it takes a deflection to appear in the EP<br />
after stimulus onset, <strong>and</strong> amplitude, usually in microvolts. "N" refers to a<br />
negative deflection <strong>and</strong> "P" to a positive deflection. A deflection, which is<br />
regularly observed in an experimental paradigm, is <strong>of</strong>ten called a component<br />
<strong>of</strong> the EP, typically measured relative to a peak in the waveform.<br />
Auditory <strong>evoked</strong> <strong>potentials</strong> (AEPs) (see Figure 1.11.) are responses<br />
following <strong>auditory</strong> stimuli. AEP components can be divided into three<br />
categories: early (50<br />
ms) components (Squires <strong>and</strong> Ollo, 1986). Furthermore, EP components are<br />
also categorized into two general categories, exogenous <strong>and</strong> endogenous.<br />
Exogenous components such as the P50 <strong>and</strong> N100 are primarily responsive to<br />
stimulus properties, such as duration, intensity, <strong>and</strong> frequency <strong>and</strong> occur<br />
whether or not the subject is paying attention to the stimuli. Abnormalities in<br />
exogenous components are consistent with abnormalities in the sensory <strong>and</strong><br />
perceptual processing <strong>of</strong> stimuli. Endogenous components such as the N200<br />
26
<strong>and</strong> P300 are affected by psychological factors, such as task relevance <strong>and</strong><br />
expectancies. Abnormalities <strong>of</strong> endogenous components may reflect<br />
abnormalities <strong>of</strong> neural structures involved in higher cognitive functions, such<br />
as attention <strong>and</strong> memory. In short, midlatency components such as the P50<br />
AEP component can be regarded as reflecting a pre-attentive process,<br />
whereas late-occurring waves such as the P300 are suggested to reflect the<br />
attentional processing <strong>of</strong> incoming stimuli.<br />
I<br />
LL<br />
MGB<br />
SO<br />
CN<br />
Auditory<br />
stimulus (S)<br />
AN<br />
amplifie<br />
Signal<br />
averager<br />
60 dBSL<br />
click<br />
Stimulus onset<br />
Cz+(A-)<br />
2 4 6 8 10 ms<br />
0.1 µV<br />
ongoing EEG<br />
Brainstem <strong>auditory</strong><br />
<strong>evoked</strong> potential<br />
(BAEP)<br />
Auditory <strong>evoked</strong> potential (AEP)<br />
(P 50)<br />
Figure 1.11. AEP gating: Auditory <strong>evoked</strong> <strong>potentials</strong><br />
Time (ms)<br />
(Adapted from Nuechterlein <strong>and</strong> Dawson 1994) (AN=<strong>auditory</strong> nerve;<br />
CN=cochlear nucleus, IC=inferior colliculus; LL=lateral lemniscus;<br />
MGB=medial geniculate body <strong>of</strong> the thalamus; SO=superior olivary nuclei)<br />
By measuring EPs to stimuli, it is possible to reach conclusions about the<br />
functioning <strong>of</strong> the different sensory pathways <strong>and</strong> the circuitry's involved in<br />
27
the potential modulation (<strong>inhibition</strong> or excitation) <strong>of</strong> the sensory information<br />
processing. In clinical practice, visual, <strong>auditory</strong>, <strong>and</strong> somatosensory stimuli<br />
are commonly used to elicit EPs that provide information regarding the<br />
integrity <strong>of</strong> sensory pathways within the nervous system (Chiappa 1983). EPs<br />
have several advantages: they have a high temporal resolution (within the<br />
ms time-range), are non-invasive <strong>and</strong> non-hazardous <strong>and</strong> hence averaging <strong>of</strong><br />
repeated presentations <strong>of</strong> stimuli can be used to enhance the signal-to-noise<br />
ratio. A disadvantage <strong>of</strong> EPs as an imaging modality is their relatively poor<br />
spatial resolution, <strong>and</strong> the consequent difficulty in defining their source(s)<br />
within the brain. Based on electrical source analysis,<br />
magnetoencephalographic (MEG) source analysis <strong>and</strong> lesion studies, it has<br />
been suggested that the sources <strong>of</strong> the N100 <strong>and</strong> P200 include temporal lobe<br />
structures (Naatanen <strong>and</strong> Picton 1987; Vaughan 1988), whereas the P300 is<br />
likely to have multiple brain electrical sources (Halgren 1986). It has been<br />
postulated that the P50 arises in medial temporal lobe structures (Bickford-<br />
Wimer et al; Adler et al 1985). This has been suggested from surface<br />
mapping studies (Woods <strong>and</strong> Wolpaw 1982). Furthermore, MEG with<br />
correlated resonance imaging suggests a superficial location in the temporal<br />
planum (Reite et al 1988). Larger P50 waves in patients with bilateral<br />
temporal cortex strokes have been found that argue against a cortical<br />
location, whereas lesions that extend to the hippocampus have been found to<br />
significantly diminish P50 amplitude that suggests a hippocampal origin<br />
(Woods et al 1984, 1987).<br />
1.2.3.2. P50 gating in human subjects: an inhibitory process<br />
In the sensory gating paradigm, an <strong>auditory</strong> click (S1) is presented to a<br />
subject, eliciting a positive deflection at 50 ms after stimulus onset. This<br />
deflection is referred to as the P50 component. After a brief interval, about<br />
500 ms, a second click (S2) elicits a much smaller P50 in normal control<br />
subjects, who are said to show normal gating. The ratio <strong>of</strong> the amplitude <strong>of</strong><br />
the second click to the first click is normally used to measure the degree <strong>of</strong><br />
gating in a subject.<br />
28<br />
Figure 1.12.<br />
AEP gating:<br />
Illustration P50 gating<br />
Deficit in a<br />
schizophrenic patient<br />
versus a healthy<br />
subject. The first<br />
waveform is the<br />
response to S1 <strong>and</strong> the<br />
second waveform is<br />
the response to S2.<br />
(Adapted from Adler et<br />
al 1998)
The reduction in P50 amplitude to the second click is much less pronounced in<br />
schizophrenic subjects (see the illustration in Figure 1.12.). In other words,<br />
they have a failure in gating (Adler et al 1982; Freedman et al 1983; Judd et<br />
al 1992). Ratios below 40% have been reported to be typical <strong>of</strong> normal<br />
subjects, <strong>and</strong> ratios above 40% are typical <strong>of</strong> schizophrenic patients (Siegel<br />
et al 1984; Waldo et al 1991). The P50 gating deficit best discriminates<br />
between control <strong>and</strong> schizophrenic patients at the vertex electrode (central<br />
zone or Cz, Nagamoto et al 1991). Furthermore, P50 gating disturbances in<br />
schizophrenic patients have only been found at the 150 <strong>and</strong> 500 ms ISIs <strong>and</strong><br />
not at the 75 ms ISI (Nagamoto et al 1989). Typical antipsychotic medication<br />
such as haloperidol does not eliminate the sensory gating differences between<br />
control <strong>and</strong> schizophrenic subjects (Freedman et al 1983; Adler et al 1990).<br />
In contrast, the atypical antipsychotic clozapine improves P50 gating to<br />
normal levels in patients (Nagamoto et al 1996, 1999; Light et al 2000).<br />
The neurophysiological defect in sensory gating may relate to a<br />
disorder in sustained attention in schizophrenia as suggested by Cullum et al<br />
(1993). They have found that the time to complete the digit cancellation test<br />
(a measure <strong>of</strong> sustained attention) correlated negatively with the gating in<br />
patients. Auditory sensory processing defects in schizophrenia appear to be<br />
independent <strong>of</strong> negative symptoms (Adler et al 1990). Finally, some<br />
paradoxical results have been obtained by Jin et al (1998): patients reporting<br />
perceptual anomalies exhibited normal gating, whereas patients who did not<br />
report perceptual anomalies showed the abnormal P50 ratios (Jin et al 1998).<br />
Light <strong>and</strong> Braff (2000) commented on these findings by arguing that selfreports<br />
in schizophrenic patients have considerable limitations (Light <strong>and</strong><br />
Braff 2000).<br />
Diminished sensory gating has also been reported to occur in about<br />
half <strong>of</strong> the first-degree relatives <strong>of</strong> schizophrenic patients (Siegel et al 1984).<br />
The likelihood <strong>of</strong> P50 gating abnormality increases as a function <strong>of</strong> both family<br />
relationship <strong>and</strong> symptomatology (Waldo et al 1988, 1995). Also, subjects<br />
with schizotypal personality disorder have reduced P50 gating (Cadenhead et<br />
al 2000). A decrease in sensory gating is found in other severely ill psychiatric<br />
patients as well, such as acutely manic patients during psychosis (Franks et al<br />
1983). As soon as their clinical condition improved following treatment with<br />
lithium carbonate, also the gating was normalized in these patients. Since<br />
such an improvement was not seen in medicated schizophrenics, gating<br />
deficits have been considered as a trait characteristic in schizophrenic<br />
patients (Baker et al 1987). Recently, taken into account the gating<br />
improvement with the atypical antipsychotic clozapine in schizophrenic<br />
patients (Nagamoto et al 1996, 1999; Light et al 2000), this consideration<br />
should be reevaluated.<br />
Besides the observed decrease in gating, schizophrenic patients also<br />
show a significantly smaller amplitude <strong>and</strong> latency <strong>of</strong> the P50 in responses to<br />
unpaired stimuli compared to controls (Adler et al 1982; Jin et al 1997). Jin et<br />
al (1997) have concluded that this reduction in the initial P50 response to S1<br />
(conditioning amplitude or CAMP) could to be an important contributor to the<br />
decrease in gating. They have found that the temporal variability (jitter) in S1<br />
P50 was significantly greater in schizophrenics than in controls <strong>and</strong> proposed<br />
that jitter may contribute to central inhibitory processes. According to Jin <strong>and</strong><br />
colleagues (Jin et al 1997; Patterson et al 2000) this 'jitter' phenomenon<br />
could be linked to the concept <strong>of</strong> 'occlusion' described by Adler et al (1982):<br />
when a neuronal population is hyperactive, its constant background discharge<br />
makes it less likely, that the majority <strong>of</strong> the neurons will respond<br />
synchronously to the stimulus being studied. This will consequently lead to<br />
29
smaller amplitudes. Adler et al (1982) have suggested that this hyperactivity<br />
is due to a lack <strong>of</strong> functional inhibitory input.<br />
1.2.3.3. P50 gating in human subjects: alternative explanations<br />
Besides inhibitory processes, alternative explanations have been given for<br />
gating, such as refractoriness (1), neuronal or receptor fatigue (2) <strong>and</strong><br />
stimulus quality adaptation due to a decrease in attention (3). First, Calloway<br />
(1973) introduced the concept <strong>of</strong> 'recovery cycles', occurring with very short<br />
ISIs between two stimuli (such as 10 ms): aggregates <strong>of</strong> cells show a short<br />
period <strong>of</strong> unresponsiveness following activation that results from membrane<br />
depolarization (also called refractory period). Several authors suggested this<br />
to be an unlikely explanation for human P50 gating, since recovery <strong>of</strong><br />
neuronal excitability has been shown to occur within 2-3 ms (Koester et al<br />
1991) <strong>and</strong> long-lasting refractoriness rarely exceed 500 ms in duration (Adler<br />
et al 1982). Moreover, the majority <strong>of</strong> the refractory period has been shown<br />
to result from inhibitory mechanisms (Eccles 1969). Secondly, neuronal or<br />
receptor fatigue could cause the decrement <strong>of</strong> the response to S2. However,<br />
the fact that gating is reduced at ISIs shorter than 100 ms in comparison to<br />
the 500 ms ISI in normal subjects is not in agreement with this suggestion<br />
(Freedman et al 1983; Franks et al 1983). Reduced gating at shorter ISIs<br />
suggests that inhibitory processes, rather than fatigue, are responsible for the<br />
gating at longer ISIs (Franks et al 1983). The third explanation for gating is<br />
'stimulus quality adaptation due to a decrease in attention'. Several<br />
researchers have considered P50 gating to be a pre-attentional phenomenon:<br />
an attention decrease observed during repeated trials did not seem to cause a<br />
decrement in P50 gating in healthy subjects (Freedman et al 1983) <strong>and</strong><br />
cortical N40-N50 gating was still observed in anesthetized animals (Bickford-<br />
Wimer et al 1990). Also, gating is not reduced during nonrapid eye movement<br />
(NREM) sleep in rats (Van Luijtelaar et al 1998). Additionally, White <strong>and</strong> Yee<br />
(1997) have found the N100 to be responsive to attentional manipulation,<br />
whereas the P50 was not affected. Finally, changes in concentration<br />
(measured by the serial subtraction test) have been found not to affect gating<br />
(Waldo <strong>and</strong> Freedman 1986). Indeed, these studies suggest that attentional<br />
processes are not involved in gating. However, Jin <strong>and</strong> Potkin (1996) have<br />
shown that gating was reduced in a visual interference condition due to a<br />
decrease in P50 amplitude to S1 <strong>and</strong> White <strong>and</strong> Yee (1997) have found P50<br />
suppression to be sensitive to an acute stressor.<br />
1.2.3.4. Repetitive stimulation <strong>and</strong> the interstimulus interval (ISI)<br />
It has been found in human subjects that the amount <strong>of</strong> sensory gating is<br />
dependent on repetitive stimulation <strong>and</strong> the interstimulus interval (ISI) (Starr<br />
et al 1997; Boutros <strong>and</strong> Belger 1999; Adler et al 1982; Freedman et al 1983).<br />
When 50 or so stimuli are given, the AEP for the first half <strong>of</strong> the stimuli<br />
is generally larger than the AEP for the second half. Several authors have<br />
suggested that sensory gating can change during a recording session (Franks<br />
et al 1983; Siegel et al 1984; Lamberti et al 1993; Clementz et al 1997).<br />
Lamberti et al (1993) have found a higher suppression during the first 30<br />
click pairs compared to the last 30 pairs during a 120 trial session. They have<br />
shown that these effects on gating were due to a gradual reduction <strong>of</strong> P50<br />
amplitude to the S1 (Lamberti et al 1993). Controversial results have been<br />
reported with respect to the effects on the amplitude to S2: Lamberti et al<br />
(1993) have found an increase, whereas Naber et al (1992) reported a<br />
30
decrease over the recording session. Clementz et al (1997) have found a<br />
more pronounced difference in suppression between schizophrenic patients<br />
<strong>and</strong> controls during the first than during the second block <strong>of</strong> trials. Cacace et<br />
al (1990) have noted that the amplitude <strong>of</strong> the P50 decreased as the number<br />
<strong>of</strong> summation increased. Also, Starr et al (1997) reported a decrease <strong>of</strong> the<br />
P50 with stimulus sequence <strong>and</strong> an increase in the human P50 after a target<br />
stimulus. In this respect, Boutros et al (1995) have distinguished between<br />
two types <strong>of</strong> gating. The first type is the more traditionally used concept:<br />
'gating out' or decreased responding to incoming irrelevant stimuli (gating is<br />
enhanced). The second type, 'gating in', when a novel stimulus is presented<br />
or a change occurs in ongoing stimuli (gating is decreased). In a recent paper<br />
by Boutros <strong>and</strong> Belger (1999), it has been suggested that the human P50 EP<br />
is sensitive to the effects <strong>of</strong> stimulus repetition <strong>and</strong> stimulus change:<br />
respectively 'gating out' <strong>and</strong> 'gating in'. Interestingly, Boutros et al. (1999)<br />
have found that schizophrenic patients have difficulty in 'gating out' irrelevant<br />
input <strong>and</strong> 'gating in' relevant input at both the early pre-attentive stage (P50)<br />
<strong>and</strong> at the later early-attentive stage (N100) as well.<br />
Several authors have found that the amount <strong>of</strong> sensory gating is<br />
dependent on the interstimulus interval (ISI). Adler et al (1982) <strong>and</strong><br />
Freedman et al (1983) have found a decrease in sensory gating with<br />
increasing ISIs (> 1 s), both in a population <strong>of</strong> untreated schizophrenic<br />
patients <strong>and</strong> healthy controls. These authors noted also that the changes in<br />
P50 gating are mainly due to changes in the amplitude <strong>of</strong> the AEP towards<br />
S2. Zouridakis <strong>and</strong> Boutros (1992) have also found that the amplitude <strong>of</strong> the<br />
P50 towards the S2 shows a progressive recovery with longer ISIs, thereby<br />
decreasing gating. Furthermore, Adler et al (1982) have found facilitation<br />
with the 50 ms ISI <strong>and</strong> an approach to recovery to initial values with the 6<br />
sec ISI in healthy human subjects. The full recovery time <strong>of</strong> the P50<br />
amplitude has been estimated at 8 s (Zouridakis <strong>and</strong> Boutros 1992).<br />
Nagamoto et al (1989) investigated short (500, 150 <strong>and</strong> 75 ms) ISIs. P50<br />
gating did occur at all three ISIs in the control group, however, the ISI was<br />
critical for the schizophrenics. More specifically, P50 gating was disturbed in<br />
patients at an ISI <strong>of</strong> 150 <strong>and</strong> 500 ms, not at an ISI <strong>of</strong> 75 ms.<br />
1.2.3.5. AEP gating in rats<br />
The EEG activity in rats is directly recorded from the brain (epidural<br />
electrodes), whereas in human subjects the EEG is recorded from the scalp.<br />
Therefore, an advantage <strong>of</strong> rat AEPs is the better signal/noise ratio. One <strong>of</strong><br />
the problems is that different groups or researchers report not always the<br />
same components <strong>of</strong> an AEP <strong>and</strong> a st<strong>and</strong>ardized electrode system such as the<br />
10-20 system in humans is lacking. The morphology <strong>of</strong> the AEP is not only<br />
dependent on the stimulus properties, but also on the localization <strong>of</strong> the EEG<br />
electrodes, whether a monopolar or bipolar recording is made <strong>and</strong> on the<br />
localization <strong>of</strong> the reference <strong>and</strong> ground electrode. Absence <strong>of</strong> a st<strong>and</strong>ardized<br />
way <strong>of</strong> measuring between groups hampers comparisons <strong>of</strong> different studies<br />
that currently still describe different components <strong>of</strong> the rat’s AEP (Adler et al<br />
1986; Miyazato et al 1996). Furthermore, it is not immediately clear what the<br />
equivalent is for the human P50 in the rat. Some (Miyazato et al 1996)<br />
propose an early component (the P13), others suggest that the cortical N40-<br />
N50 is the equivalent (Adler et al 1986). The later authors also propose that<br />
the rat P20-N40 wave, recorded from the cornu ammonis (CA) 3 <strong>and</strong> 4<br />
regions <strong>of</strong> the hippocampus (HPC), shows suppression <strong>of</strong> response to<br />
repeated stimuli similar to that <strong>of</strong> the human P50 wave.<br />
31
1.2.3.6. Neural substrate <strong>of</strong> AEP gating<br />
Especially the hippocampus (HPC) seems to be a very important brain area in<br />
AEP gating (for review: Adler et al 1998). The HPC is divided into the dentate<br />
gyrus (DG), which contains the granule cells, <strong>and</strong> areas CA1-CA4, which<br />
contain the pyramidal cells (see Figure 1.13.). It also has contiguous<br />
neocortical areas that are closely related to its functioning: the subicular<br />
complex <strong>and</strong> the entorhinal cortex (EC). The EC receives polymodal sensory<br />
input from association areas throughout the neocortex. Directly through the<br />
perforant pathway (PP) <strong>and</strong> indirectly through the DG mossy fiber (MF)<br />
projections, the EC conveys this sensory information to the pyramidal cells <strong>of</strong><br />
the CA3 region (for review also see Amaral <strong>and</strong> Witter 1995). Besides the<br />
cortical input via the primary lemniscal pathway, the CA3 region also receives<br />
inputs from non-lemniscal pathways via the brainstem. Brain stem neurons<br />
project directly to CA3 from the noradrenergic locus coeruleus (LC) <strong>and</strong> the<br />
serotonergic raphe nucleus (RN). Additionally, the brain stem reticular<br />
formation influences the HPC indirectly, via the cholinergic projection from the<br />
medial septum (Bickford et al 1993). Finally, the CA3 region projects to CA1<br />
via the Schaffer collaterals (Ishizuka et al 1990) that reach the subicular<br />
complex. A second target <strong>of</strong> the CA3 is the lateral septum (Swanson 1980).<br />
Thus, the CA3 is a major point <strong>of</strong> convergence for cortical <strong>and</strong> brainstem<br />
inputs from both the lemniscal <strong>and</strong> non-lemniscal <strong>auditory</strong> pathways (see<br />
Figure 1.13.) <strong>and</strong> this area has been suggested to be a modulator in the<br />
sensory gating process (Bickford-Wimer et al 1990; Miller <strong>and</strong> Freedman<br />
1995; Stevens et al 1998; Adler et al 1998).<br />
Adler et al (1998) have proposed a model that describes the process<br />
that is suggested to give rise to P50 gating. S1 is thought to activate CA3<br />
pyramidal cells through the PP input from the EC <strong>and</strong> the granule cell input<br />
from the DG. The cholinergic input from the medial septum is also activated<br />
so that there is a burst <strong>of</strong> activity in the pyramidal cells (Miller <strong>and</strong> Freedman<br />
1995). Consequently, a large portion <strong>of</strong> CA3 pyramidal neurons is thought to<br />
be excited by S1. Then, interneurons in the HPC have been suggested to<br />
inhibit CA3 pyramidal cells during the interclick interval (Miller <strong>and</strong> Freedman<br />
1995). Adler et al (1998) have speculated that the response to S2 is probably<br />
diminished due to an <strong>inhibition</strong> <strong>of</strong> glutamate release from the granule cell MF<br />
synapses <strong>and</strong> from recurrent pyramidal cell synapses. Therefore, S2 is<br />
thought to excite a much more restricted population <strong>of</strong> neurons. The authors<br />
propose that GABA could be involved in this <strong>inhibition</strong> (Adler et al 1998).<br />
Although this is an interesting model for P50 gating, only one study provides<br />
evidence confirming the involvement <strong>of</strong> GABA in gating. Hershman et al<br />
(1995) have shown that GABA-B antagonists such as CGP-35348 can diminish<br />
gating in the rat hippocampus by increasing the amplitude to S2.<br />
Moxon et al (1999) have studied single-unit neuron firing in response to<br />
<strong>auditory</strong> clicks. They have found that the response to the clicks was most<br />
pronounced in the brainstem reticular nucleus <strong>and</strong> the medial septal nucleus,<br />
while relatively few neurons responded in the CA3 <strong>and</strong> the <strong>auditory</strong> cortex.<br />
Furthermore, these authors have found support for the hypothesis that<br />
inhibitory gating originates in the non-lemniscal pathway <strong>and</strong> not in cortical<br />
areas <strong>of</strong> the rat brain. Brainstem reticular nucleus neurons showed the<br />
greatest gating <strong>of</strong> local AEPs, while the <strong>auditory</strong> cortex showed the least.<br />
<strong>Gating</strong> <strong>of</strong> the CA3 response was significantly correlated with gating in the<br />
medial septal nucleus <strong>and</strong> brainstem reticular nucleus, but not the <strong>auditory</strong><br />
cortex. In another study, using Fos-immunoreactivity, it has been shown that<br />
besides the medial also the lateral septum is involved in AEP gating (Van<br />
32
Luijtelaar et al unpublished data). As has already been described before<br />
(paragraph 1.1), the VTA sends DA projections to the hippocampal DG, lateral<br />
septum (Swanson 1982) <strong>and</strong> cortical areas (e.g. EC) (Berger et al 1976;<br />
Björklund <strong>and</strong> Lindvall 1984; Fuxe et al 1985; Descarries et al 1987). So, a<br />
modulation <strong>of</strong> gating could take place via these DA fibers to the DG <strong>and</strong> EC.<br />
EC<br />
Dendate<br />
gyrus<br />
Entorhinal<br />
cortex (EC)<br />
Cortical<br />
association<br />
area<br />
PP<br />
Primary<br />
<strong>auditory</strong><br />
cortex<br />
MF<br />
PP<br />
DG<br />
to Subicular complex<br />
DA<br />
DA<br />
Primary<br />
lemniscal<br />
pathway<br />
CA1<br />
VTA<br />
ACH<br />
MF<br />
CA1<br />
CA3<br />
Medial septum<br />
Brainstem RF<br />
IC LL VCN DCN<br />
Figure 1.13. AEP gating: Circuitry<br />
Lateral septum<br />
LC<br />
CA3<br />
NE<br />
Non-lemniscal<br />
pathway<br />
SHP<br />
RN<br />
5-HT<br />
DCN=dorsal cochlear nuclei; DG=dentate gyrus; EC=entorhinal<br />
cortex IC=inferior colliculus; LC=locus ceruleus; LL=lateral<br />
lemniscus; MF=mossy fibers; PP=perforant pathway; RF=reticular<br />
formation; RN=raphe nuclei; SHP=septo-hippocampal pathway;<br />
VCN=ventral cochlear nuclei; Neurotransmitters: ACH=acetylcholine;<br />
DA=dopamine; NE=noradrenaline; 5-HT=5-Hydroxytryptamine<br />
(serotonin) (Adapted from Adler et al 1998)<br />
33
1.2.3.7. Pharmacology <strong>of</strong> AEP gating<br />
1. Dopamine Effects <strong>of</strong> DA on AEP gating are presented in Table 1.2. Although<br />
the evidence for the involvement <strong>of</strong> DA in AEP gating is not as extensive as<br />
for PPI, DA seems to play a modulatory role in AEP gating as well. DA<br />
agonists such as bromocriptine <strong>and</strong> amphetamine have been found to reduce<br />
P50 gating in healthy human subjects (respectively, Adler et al 1994 <strong>and</strong><br />
Light et al 1999). Similar results have been obtained in rats: apomorphine<br />
<strong>and</strong> amphetamine reduced gating <strong>of</strong> the cortical N40-N50 component (Adler<br />
et al 1986; Stevens et al 1995, 1996). Also, the gating <strong>of</strong> the hippocampal<br />
P20-N40 was significantly reduced after amphetamine (Bickford-Wimer et al<br />
1990). The indirect DA agonist amphetamine did not affect gating in neonatal<br />
DA lesioned rats, whereas the direct DA agonist apomorphine reduced gating<br />
in both sham <strong>and</strong> lesioned animals (Stevens et al 1996). Furthermore,<br />
amphetamine has been proposed to reduce gating through its effects on<br />
alpha- <strong>and</strong> beta- adrenergic receptors <strong>and</strong> DA D1 receptors (Stevens et al<br />
1991). This study showed that adrenergic effects were predominantly on the<br />
amplitude to S2 (on the testing amplitude or TAMP), whereas DA effects were<br />
on the amplitude to S1 (the conditioning amplitude or CAMP). The role <strong>of</strong> DA<br />
activity at D2 receptors is less evident, since amphetamine effects were only<br />
partially blocked by the D2 antagonist sulpiride (Stevens et al 1991) <strong>and</strong> the<br />
D2/D3 agonist 7-OH-DPAT did not reduce gating (Ellenbroek et al 1999).<br />
Table 1.2. Dopaminergic effects on AEP gating<br />
Species Area <strong>Gating</strong>↓ Reversal Reference<br />
DA<br />
Rat ⎯ amphetamine (DA ag) Adler et al '86<br />
Rat ⎯ amphetamine (DA ag)<br />
hippocampal gating<br />
haloperidol Bickford-Wimer et<br />
al '90<br />
Human ⎯ bromocriptine (DA-ag) Adler et al '94<br />
Rat ⎯ amphetamine (DA ag) nicotine (blocked by dtubocurarine)<br />
Stevens et al '95<br />
Human ⎯ amphetamine (DA-ag) Light et al '99<br />
Rat<br />
⎯<br />
DA RECEPTOR<br />
SUBTYPES<br />
amphetamine (DA ag) phentolamine (α anta)<br />
timolol (β anta)<br />
SCH 23390 (D1 anta)<br />
sulpiride (D2 anta,<br />
trend)<br />
Stevens et al '91<br />
Rat ⎯ 7-OH-DPAT (D2/3 ag) Ellenbroek et al '99<br />
6-OHDA EFFECTS<br />
Rat ⎯ apomorphine (DA ag):<br />
lesioned = sham<br />
amphetamine (DA ag):<br />
lesioned sham<br />
Effects are not significant when printed in bold- italic.<br />
ag=agonist; anta=antagonist; DA=dopamine.<br />
Stevens et al '96<br />
2. Other neurotransmitters One <strong>of</strong> the most important neurotransmitter<br />
systems in AEP gating is thought to be the nicotinic cholinergic system (for<br />
review see Adler et al 1998). It has been suggested that heavy smoking in<br />
34
schizophrenics may represent a form <strong>of</strong> self-medication. Scopolamine <strong>and</strong><br />
mecamylamine, which block muscarinic <strong>and</strong> high affinity nicotinic receptors,<br />
respectively, did not alter the inhibitory gating <strong>of</strong> the rat hippocampal P20-<br />
N40. However, alpha-bungarotoxin, which blocks a lower affinity population <strong>of</strong><br />
nicotinic receptors (alpha-7), did reduce sensory gating (Luntz-Leybman et al<br />
1992). Cholinergic afferents, by activating these alpha-bungarotoxin-sensitive<br />
receptors, may excite inhibitory neurons, which then discharge in prolonged<br />
fashion to produce a long-lasting <strong>inhibition</strong> <strong>of</strong> the response <strong>of</strong> pyramidal<br />
neurons to afferents from the PP (Miller <strong>and</strong> Freedman 1995). Freedman et al<br />
(1995) have found diminished alpha-bungarotoxin labeling <strong>of</strong> interneurons in<br />
postmortem samples <strong>of</strong> hippocampus from schizophrenic patients. However,<br />
nicotine does not appear to have long-lasting therapeutic effects on gating,<br />
probably because <strong>of</strong> a desensitization <strong>of</strong> the nicotinergic receptors (Griffith et<br />
al 1993, 1996; Griffith <strong>and</strong> Freedman 1995). These authors have done<br />
several experiments that provide evidence for the suggestion that<br />
desensitization <strong>of</strong> the nicotinergic receptors reduce the therapeutic effects <strong>of</strong><br />
nicotine. To resensitize the nicotinergic receptors, subjects were allowed to<br />
have a period <strong>of</strong> NREM sleep (cholinergic neurons cease firing). A short<br />
normalization following NREM sleep was observed in patients. Applying a<br />
nicotine transdermal patch prior to the experiment, however, could prevent<br />
this normalization.<br />
Besides cholinergic <strong>and</strong> DA effects on AEP gating, a reduction in glutamate<br />
activity in the brain is thought to reduce gating. Non-competitive NMDAreceptor<br />
antagonists such as PCP <strong>and</strong> MK-801 significantly reduced cortical<br />
<strong>and</strong> hippocampal gating in rats (Adler et al 1986; Miller et al 1992). Also,<br />
serotonin (5-HT) seems to be involved. Systemic administration <strong>of</strong> the 5-HT2receptor<br />
antagonist ketanserin reduced sensory gating. In contrast, the 5-<br />
HT2-receptor agonist DOI significantly improved gating. In addition, DOI<br />
antagonized the disruption <strong>of</strong> gating induced by administration <strong>of</strong><br />
amphetamine (Johnson et al 1989).<br />
3. Non-pharmacological manipulations Currently, only one study by Stevens<br />
et al (1997) has reported the effect <strong>of</strong> isolation rearing on AEP gating in rats.<br />
Socially reared rats showed substantial gating, while isolation-reared rats<br />
failed to gate. The isolation-reared rats were given nicotine bitartrate that<br />
enhanced the gating for 60 min. By contrast, haloperidol failed to normalize<br />
gating in these rats. <strong>Gating</strong> has also been found to be disrupted in maternally<br />
deprived animals (Ellenbroek et al unpublished data). Interestingly, DBA/2<br />
mice, an inbred strain with reduced hippocampal alpha-7 nicotinergic<br />
receptors, showed hippocampal gating deficits (Stevens <strong>and</strong> Wear 1997) that<br />
could be normalized with the nicotinic agonist ABT418. Finally, in a previous<br />
study by Van Luijtelaar et al (1998), gating was studied during three different<br />
vigilance states: passive wakefulness, REM <strong>and</strong> non-REM sleep. Although<br />
significant gating was observed in all three conditions, gating was significantly<br />
reduced during REM sleep as compared to the passive wakefulness state (Van<br />
Luijtelaar et al 1998).<br />
1.2.4. SIMILARITIES AND DIFFERENCES BETWEEN PPI AND AEP GATING<br />
Various similarities <strong>and</strong> differences have been found between PPI <strong>and</strong> AEP<br />
gating based on parametric variables, findings in patients, data on the neural<br />
substrate <strong>and</strong> pharmacological manipulations.<br />
35
1.2.4.1. Similarities<br />
In the early 1990's, it was suggested that both gating measures involve<br />
similar mechanisms (Ellenbroek <strong>and</strong> Cools 1990; Freedman <strong>and</strong> Mirsky 1991;<br />
Braff 1993). A general similarity between both processes is that they reflect<br />
long-lasting inhibitory processes in the <strong>auditory</strong> pathway.<br />
<strong>Gating</strong> deficits in both PPI <strong>and</strong> AEP gating in schizophrenic patients<br />
have been suggested to be dependent on genetic factors <strong>and</strong> have been<br />
referred to as a trait deficit or biological marker for schizophrenia spectrum<br />
disorders. Such suggestions are based on studies in which gating failure was<br />
reported in asymptomatic family members <strong>and</strong> subjects with schizotypical<br />
personality disorder (Waldo et al 1988, 1995; Cadenhead 1993, 1999, 2000).<br />
Furthermore, both PPI <strong>and</strong> AEP gating deficits in patients have been found to<br />
normalize with the atypical antipsychotic clozapine, whereas no improvement<br />
was found with typical antipsychotics such as haloperidol (Freedman et al<br />
1983; Adler et al 1990; Nagamoto 1996, 1999; Kumari et al 1999; Light et al<br />
2000)<br />
When comparing the neural substrate <strong>of</strong> both gating processes based<br />
on rat studies, the septo-hippocampal system seems to be an important brain<br />
area in both PPI (Caine et al 1992; Koch 1996) <strong>and</strong> AEP gating (Bickford-<br />
Wimer et al 1990; Miller <strong>and</strong> Freedman 1995; Stevens et al 1998).<br />
Some final common results have been obtained in pharmacological<br />
studies. With respect to pharmacological effects in rats, it has been shown<br />
that systemically injected DA agonists <strong>and</strong> non-competitive NMDA antagonists<br />
decrease PPI <strong>and</strong> AEP gating (Mansbach et al 1988; Swerdlow et al 1996;<br />
Adler et al 1986; Bickford-Wimer et al 1990; Stevens et al 1995; Geyer et al<br />
1989; Mansbach et al 1991; Mansbach <strong>and</strong> Geyer 1991; Adler et al 1986;<br />
Miller et al 1992). In contrast, nicotinergic agents have been found to<br />
temporarily restore PPI <strong>and</strong> AEP gating deficits (Kumari et al 1996; Stevens<br />
et al 1997; Stevens <strong>and</strong> Wear 1997).<br />
1.2.4.2. Differences<br />
Lately, there has been increasing evidence that both paradigms differ in many<br />
aspects <strong>and</strong> it has therefore been suggested that both gating measures might<br />
reflect different inhibitory processes in the brain (Schwarzkopf et al 1993;<br />
Ellenbroek et al 1999). The experimental conditions in both the PPI <strong>and</strong> AEP<br />
gating paradigm differ in several ways. First, in PPI the output parameter is a<br />
reflex, whereas in AEP gating the EEG/AEP is registered. Secondly, the stimuli<br />
presented in both paradigms differ. Third, <strong>inhibition</strong> in the PPI paradigm is<br />
maximal at ISIs <strong>of</strong> 100-120 ms (Graham <strong>and</strong> Murray 1977; Braff et al 1978)<br />
<strong>and</strong> reduced at an ISI <strong>of</strong> 500 ms in healthy subjects (H<strong>of</strong>fman <strong>and</strong> Searle<br />
1968). In normal subjects, AEP gating occurs at ISIs <strong>of</strong> 75, 150 <strong>and</strong> 500 ms<br />
<strong>and</strong> facilitation with the 50 ms ISI (Adler et al 1982; Nagamoto et al 1989).<br />
Moreover, gating is only disturbed at the 150 <strong>and</strong> 500 ms ISIs in<br />
schizophrenic patients (Nagamoto et al 1989). In contrast, these patients<br />
have a significant reduction in PPI at the 100-120 ms ISIs (*). An interesting<br />
finding is that gating parameters in the AEP gating <strong>and</strong> PPI paradigms have<br />
been found to be not correlated in rats (Ellenbroek et al 1999), which is in<br />
agreement with findings <strong>of</strong> Schwarzkopf et al (1993) in humans.<br />
Several pharmacological studies have found differential effects <strong>of</strong> drugs<br />
on PPI <strong>and</strong> AEP gating. First, the DA D2/D3 agonist 7-OH-DPAT has been<br />
found to disrupt PPI (Caine et al 1995; Varty <strong>and</strong> Higgens 1998; Ellenbroek et<br />
al 1999), whereas no effect was found on AEP gating (Ellenbroek et al 1999).<br />
36
Secondly, the PCP-induced reduction in AEP gating could be antagonized by<br />
haloperidol (Adler et al 1986). However, haloperidol did not antagonize<br />
effects <strong>of</strong> PCP on PPI (Geyer et al 1989; Keith et al 1991). Third, the 5-HT2receptor<br />
agonist DOI decreased PPI <strong>and</strong> increased AEP gating in rats (Sipes<br />
<strong>and</strong> Geyer 1994; Johnson et al 1998). Finally, apomorphine differentiated<br />
between neonatal DA lesioned rats <strong>and</strong> sham lesioned rats in the PPI<br />
paradigm (Schwarzkopf et al 1992), whereas no differentiation <strong>of</strong> the<br />
apomorphine effect between both groups was found in the AEP gating<br />
paradigm (Stevens et al 1996).<br />
1.2.5. CONCLUSIONS<br />
Given the above mentioned considerations it can be concluded that PPI <strong>and</strong><br />
AEP gating have neural substrates that show overlap on certain parts, but<br />
also differ on other parts <strong>of</strong> the neural substrate.<br />
Several questions remain to be answered<br />
1.It is still not clear what the equivalent is for the human P50 in the<br />
rat. Some (Miyazato et al 1996) propose an early component (the<br />
P13), others suggest that the cortical N40-N50 is the equivalent<br />
(Adler et al 1986). Considering these limitations, more research<br />
should be focussed on comparing properties <strong>of</strong> the human P50 <strong>and</strong><br />
<strong>of</strong> rat midlatency AEP components. It is <strong>of</strong> particular importance to<br />
investigate which <strong>of</strong> the above mentioned rat AEP components<br />
respond in a similar fashion to certain experimental manipulations.<br />
2.With respect to PPI, effects <strong>of</strong> the individual DA systems (ventral<br />
<strong>and</strong> dorsal striatum) have been studied. However, also the role <strong>of</strong><br />
the DA balance between both DA systems could be an important<br />
factor in the modulation <strong>of</strong> gating in the PPI <strong>and</strong> AEP gating<br />
paradigms.<br />
3.It has been shown that DA D2 receptors in the NAC play a<br />
prominent role in PPI. It is not clear whether these NAC receptors<br />
are involved in AEP gating as well. Systemic drug manipulations,<br />
however, do not point in this direction, since amphetamine effects<br />
on AEP gating were only partially antagonized by the D2 antagonist<br />
sulpiride (Stevens et al 1991) <strong>and</strong> the D2 agonist 7-OH-DPAT did<br />
not reduce AEP gating (Ellenbroek et al 1999). These discrepancies<br />
should be studied further. Therefore, it is necessary to investigate<br />
effects on AEP gating <strong>of</strong> drugs acting on D2 receptors in the NAC.<br />
4.Systemic effects <strong>of</strong> non-competitive NMDA receptor antagonists<br />
have reliably shown to decrease PPI. However, effects <strong>of</strong> such<br />
drugs on AEP gating have only been studied twice <strong>and</strong> in the same<br />
laboratory. A disruption <strong>of</strong> cortical AEP gating by PCP was found<br />
<strong>and</strong> haloperidol restored this deficit (Adler et al 1986). Since PCP is<br />
also known as a DA reuptake inhibitor, these effects could be<br />
explained in terms <strong>of</strong> DA effects. Therefore, it is <strong>of</strong> interest to study<br />
the influence <strong>of</strong> a more specific NMDA antagonistic drug in order to<br />
compare effects <strong>of</strong> such a drug on PPI <strong>and</strong> AEP gating.<br />
37
1.3. RAT GENOTYPES WITH DIFFERENT DA CHARACTERISTICS<br />
1.3.1. APO-SUS AND APO-UNSUS<br />
A non-invasive approach in studying the role <strong>of</strong> the DA system in gating is to<br />
investigate information processing in rat genotypes that differ in distinct DA<br />
systems. Two ratlines that show such clear differences are the apomorphine<br />
unsusceptible (APO-UNSUS) <strong>and</strong> susceptible (APO-SUS) rats. These rat<br />
genotypes have been obtained by pharmacogenetic selection.<br />
"By means <strong>of</strong> pharmacogenetic selection, APO-SUS <strong>and</strong><br />
APO-UNSUS were developed. For a detailed description <strong>of</strong> the<br />
original development <strong>of</strong> the APO-SUS <strong>and</strong> APO-UNSUS lines,<br />
the reader is referred to Cools et al (1990). Briefly, all males<br />
<strong>and</strong> females <strong>of</strong> a generation were submitted to the<br />
apomorphine test <strong>and</strong> the mean gnawing score to the DA<br />
agonist apomorphine (1.5 mg/kg, SC) per gender <strong>and</strong> litter was<br />
determined. Out <strong>of</strong> the four highest male APO-SUS litters <strong>and</strong><br />
female APO-SUS litters the nine highest scoring males <strong>and</strong><br />
females were selected for the next APO-SUS generation.<br />
Likewise, out <strong>of</strong> the four lowest male APO-UNSUS litters <strong>and</strong><br />
female APO-UNSUS litters, the nine lowest scoring males <strong>and</strong><br />
females were selected for the next APO-UNSUS generation.<br />
Brother-sister pairings were prevented for each generation"<br />
(Ellenbroek et al 2000).<br />
The APO-SUS <strong>and</strong> APO-UNSUS show opposite characteristics concerning<br />
certain aspects <strong>of</strong> their pharmacology, behavior <strong>and</strong> neuroendocrinological<br />
<strong>and</strong> immunological systems (for review: Cools <strong>and</strong> Gingras 1998). Evidence<br />
for differences between APO-SUS <strong>and</strong> APO-UNSUS in DA activity in various<br />
brain areas was provided through assessment <strong>of</strong> pharmacological, behavioral<br />
<strong>and</strong> biochemical measures (Cools et al 1990, 1997; Rots et al 1996;<br />
Ellenbroek et al 2000).<br />
First, APO-SUS rats display a high gnawing response following an<br />
injection <strong>of</strong> an intermediate dose <strong>of</strong> apomorphine <strong>and</strong> therefore these rats are<br />
characterized by a low DA activity in the dorsal striatum (caudate putamen,<br />
CPu). In contrast, the APO-UNSUS display a low gnawing response to the<br />
same dose <strong>of</strong> apomorphine <strong>and</strong> are characterized by a high DA activity in the<br />
dorsal striatum (Cools et al 1990; Ellenbroek et al 2000). This has been<br />
confirmed biochemically by Rots et al (1996). APO-SUS rats are characterized<br />
by higher tyrosine hydroxylase (TH, the rate limiting enzyme in DA synthesis)<br />
mRNA levels in the SNc <strong>and</strong> a higher density <strong>of</strong> D2/D3 binding sites <strong>and</strong> D1<br />
receptor mRNA in the SNc projection area (predominantly the dorsal<br />
striatum), suggesting an enhanced DA responsiveness for the nigrostriatal<br />
system.<br />
Secondly, based on the assessment <strong>of</strong> the locomotor activity on the<br />
open-field following a challenge, the DA activity <strong>of</strong> the ventral striatum has<br />
been established (see Cools et al 1990, 1991, <strong>and</strong> 1997). APO-SUS rats show<br />
significantly more novelty-induced ambulatory behavior, habituate much<br />
slower <strong>and</strong> are more susceptible to the behavioral effects <strong>of</strong> intermediate<br />
doses <strong>of</strong> amphetamine than the APO-UNSUS. Therefore, it is thought that<br />
APO-SUS rats have a higher DA reactivity <strong>of</strong> the mesolimbic system as<br />
compared to the APO-UNSUS (Cools et al 1990).<br />
38
Interestingly, Ellenbroek et al (1995) have found that APO-SUS rats<br />
are characterized by diminished PPI as compared to rats <strong>of</strong> the APO-UNSUS<br />
genotype. Other similarities with schizophrenia have also been described by<br />
these authors: APO-SUS rats have elevated levels <strong>of</strong> mRNA for TH in the SNc<br />
(Cools et al 1994); a heightened response to novelty (hyperarousal) (Cools et<br />
al 1990); a reduced sensitivity for rheumatoid arthritis (Van der Langerijt et<br />
al 1994) <strong>and</strong> a cognitive deficit in latent <strong>inhibition</strong> (Ellenbroek et al 1995). In<br />
sum, it has been suggested that the APO-SUS may be an interesting model<br />
for psychosis-prone patients.<br />
Another difference between APO-SUS <strong>and</strong> APO-UNSUS is the incidence<br />
<strong>of</strong> spike-wave-discharges (SWDs) in the EEG (Cools <strong>and</strong> Peeters 1991) (see<br />
example <strong>of</strong> <strong>and</strong> SWD in Figure 1.14.). APO-SUS rats have more SWDs at the<br />
age <strong>of</strong> six months as compared to the APO-UNSUS. Buzsáki et al (1990) have<br />
proposed that the SWD incidence is related to differences in DA properties<br />
between rat strains. For instance, Fisher 344 rats show more SWDs while<br />
these rats also have a higher TH activity <strong>and</strong> D2 binding values in the SNc<br />
<strong>and</strong> dorsal striatum as compared to Buffalo rats (Buzsáki et al 1990b).<br />
Therefore, it has been suggested that the difference in SWDs between APO-<br />
SUS <strong>and</strong> APO-UNSUS rats is also dependent on the DA properties in these<br />
rats (Cools <strong>and</strong> Peeters 1992).<br />
Figure 1.14.<br />
SWD:<br />
Example<br />
1.3.2. WAG/RIJ AND ACI RATS<br />
1 sec<br />
Coenen, Van Luijtelaar <strong>and</strong> colleagues have been investigating one particular<br />
rat genotype, the WAG/Rij rats, which show some resemblance with human<br />
subjects with generalized absence epilepsy in EEG paroxysms <strong>and</strong> clinical<br />
concomitants. The WAG/Rij rat is therefore considered as a genetic animal<br />
model for absence epilepsy (for review Coenen et al 1992; Van Luijtelaar <strong>and</strong><br />
Coenen 1997). All adult WAG/Rij rats show spontaneous occurring SWDs with<br />
a frequency <strong>of</strong> 7 to 9 Hz <strong>and</strong> a mean duration <strong>of</strong> 5 sec (Van Luijtelaar <strong>and</strong><br />
Coenen 1986). These SWDs have been found to occur predominantly during<br />
intermediate levels <strong>of</strong> vigilance (Coenen et al 1990; Drinkenburg et al 1991).<br />
ACI rats <strong>of</strong>ten serve as a control rat strain for the WAG/Rij rats, since these<br />
rats appear to be virtually free <strong>of</strong> SWDs (Inoue et al 1990).<br />
A genetic study (Peeters et al 1990a), in which the SWD incidence was<br />
determined in F1 hybrids (WAG/Rij <strong>and</strong> ACI crossbreeding) indicated a<br />
dominant inheritance <strong>of</strong> SWD occurrence. This is in agreement with findings<br />
in human absence epilepsy (Metrakos <strong>and</strong> Metrakos 1970). In addition, based<br />
on data on the inheritance <strong>of</strong> SWD number <strong>and</strong> duration, Peeters et al<br />
(1990a) have concluded that the actual amount <strong>of</strong> SWDs is dependent on<br />
more than one gene.<br />
SWDs are thought to be due to synchronized responses <strong>of</strong> thalamocortical<br />
neurons (TC). This synchronization process is considered to be caused<br />
by the GABA-mediated output from the reticular thalamic nucleus (RTN)<br />
(Steriade <strong>and</strong> Llinas 1988). Both the GABAergic <strong>and</strong> glutamatergic systems<br />
39
have been implicated in SWDs. Pharmacological studies in WAG/Rij's have<br />
shown that the GABA agonist muscimol increases, whereas the GABA<br />
antagonist bicuculline decreases SWDs (Peeters et al 1989a). Furthermore,<br />
the non-competitive NMDA antagonist MK-801 has been found to decrease<br />
SWD number (Peeters et al 1989b). In contrast, NMDA has been found to<br />
enhance epileptic activity (Peeters et al 1990b). However, as was also<br />
described in the previous section, DA could play a role in SWDs as well. There<br />
is an indication that DA might also play a modulatory role in the SWD<br />
incidence in WAG/Rij rats, since the DA antagonist fluanisone has been shown<br />
to induce a large increase in spike-wave activity in WAG/Rij's (Inoue et al<br />
1994)<br />
1.3.3. CONCLUSIONS<br />
APO-SUS <strong>and</strong> APO-UNSUS rat genotypes have different DA properties <strong>and</strong><br />
also differ in information processing. APO-SUS rats show disturbances in PPI<br />
<strong>and</strong> latent <strong>inhibition</strong>, which makes these rats a good model for schizophrenia.<br />
It has been suggested that certain DA properties in particular rat<br />
genotypes occur in parallel with spike-wave phenomena in the EEG. So, it can<br />
be suggested that rats that differ in SWD incidence might also have different<br />
DA properties. Therefore, WAG/Rij's <strong>and</strong> ACI that vary in SWD incidence,<br />
could also posses different DA characteristics.<br />
Several questions remain to be answered<br />
1.AEP gating has not yet been studied in the APO-SUS <strong>and</strong> APO-<br />
UNSUS rats. Therefore, the question is whether APO-SUS rats can<br />
also be considered as a good model for AEP gating disturbances<br />
seen in schizophrenic patients.<br />
2.The question is whether other rat genotypes, besides the APO-<br />
SUS <strong>and</strong> APO-UNSUS, also differ in DA properties. Given the<br />
difference in SWD incidence in WAG/Rij’s <strong>and</strong> ACI rats <strong>and</strong> the<br />
involvement <strong>of</strong> DA in SWDs, it is can be suggested that the<br />
WAG/Rij <strong>and</strong> ACI strains might also differ in DA properties<br />
3.When APO-SUS, APO-UNSUS, WAG/Rij <strong>and</strong> ACI rat differ in DA<br />
balance between the ventral <strong>and</strong> dorsal striatum, it is <strong>of</strong> interest to<br />
compare to compare these rats in the PPI <strong>and</strong> AEP gating<br />
paradigms.<br />
1.4. RATIONALE AND OBJECTIVES OF THE PRESENT STUDY<br />
The goal <strong>of</strong> the present thesis is to analyze (1) to what extent the various DA<br />
subsystems in the brain are involved in the information processing assessed<br />
in the PPI <strong>and</strong> AEP gating paradigms <strong>and</strong> (2) to what extent these paradigms<br />
represent similar or different aspects <strong>of</strong> information processing.<br />
In humans, the P50 component has been shown to be dependent on<br />
repetitive stimulation. Particularly, the amplitude to S1 has been found to<br />
reduce with repeated stimulus presentation. Furthermore, it has been shown<br />
human P50 gating decreases with longer interclick intervals (ISIs) due to an<br />
increase in the response to S2. Since it is not immediately clear what the<br />
equivalent is for the human P50 in the rat, it was determined which<br />
40
midlatency cortical AEP components in the rat are also affected by repetitive<br />
stimulation <strong>and</strong> the ISI in a similar fashion. Results <strong>of</strong> this experiment are<br />
presented in chapter 2.<br />
A relationship between the incidence <strong>of</strong> spike-wave discharges (SWDs)<br />
<strong>and</strong> DA activity in circumscribed brain regions has been proposed. Therefore,<br />
differences in SWD incidence could reflect differences in DA properties. This<br />
holds true for the apomorphine susceptible (APO-SUS) <strong>and</strong> unsusceptible<br />
(APO-UNSUS) rat genotypes. The DA properties <strong>of</strong> the APO-SUS rat genotype<br />
have been suggested to contribute to the high incidence <strong>of</strong> SWDs. Indeed,<br />
APO-UNSUS rats, characterized by opposite DA properties, show considerably<br />
less SWDs than APO-SUS rats. To further test this hypothesis, effects on SWD<br />
incidence <strong>of</strong> the DA antagonist haloperidol was tested in these two genotypes.<br />
Also, the WAG/Rij (an animal model for absence epilepsy) <strong>and</strong> the nonepileptic<br />
ACI strains were included in the experiment. Chapter 3 presents the<br />
results <strong>of</strong> this study in which it was investigated whether the four types <strong>of</strong><br />
animals form a continuum with respect to the incidence <strong>of</strong> SWDs at baseline<br />
<strong>and</strong> following haloperidol, <strong>and</strong> probably with respect to the DA activity as<br />
well.<br />
In order to firmly conclude that indeed the four rat genotypes differ in<br />
their DA properties, the activity <strong>of</strong> the DA system in various brain structures<br />
was established through assessment <strong>of</strong> behavioral responses. In chapter 4,<br />
we therefore present the study on these behavioral responses in the four rat<br />
genotypes. First, the DA activity in the dorsal striatum (caudate-putamen,<br />
CPu) was measured in a stereotypy paradigm. Secondly, novelty induced<br />
spontaneous activity <strong>and</strong> amphetamine induced locomotor stimulation was<br />
measured on an open-field to determine the DA reactivity in the ventral<br />
striatum (nucleus accumbens, NAC).<br />
Since the DA system has been shown to play a prominent role in PPI<br />
<strong>and</strong> also is involved in AEP gating, the next step was to study whether the<br />
four rat genotypes that differ in their DA properties would also show<br />
differences in the two information processing paradigms. In chapter 5, the<br />
results <strong>of</strong> this study are presented.<br />
It has been suggested that DA D2 receptors in the mesolimbic DA<br />
terminal region in the NAC regulate PPI. For AEP gating this involvement is by<br />
no means clear. Chapter 6 deals with this question. Here, the effects <strong>of</strong> NAC<br />
microinjections <strong>of</strong> the DA D2/D3 agonist quinpirole on both cortical <strong>and</strong><br />
hippocampal AEP gating are presented. Furthermore, the results on the<br />
possible antagonistic effect <strong>of</strong> the DA D2 antagonist haloperidol are shown.<br />
Considering that two subregions <strong>of</strong> the NAC, the shell <strong>and</strong> the core, have<br />
been found to differ anatomically as well as functionally, it was decided to<br />
separately analyze the effects <strong>of</strong> quinpirole on AEP gating in both these NAC<br />
sites.<br />
Besides the effects <strong>of</strong> the DA system on both PPI <strong>and</strong> AEP gating, also<br />
a reduction in glutamatergic activity in the brain has been shown to be an<br />
important factor in gating mechanisms. In chapter 7, therefore, we present<br />
the study on the effects <strong>of</strong> the non-competitive NMDA receptor antagonist<br />
ketamine on both types <strong>of</strong> gating. The main aim <strong>of</strong> this study was to<br />
determine whether the glutamatergic system is differentially involved in AEP<br />
gating <strong>and</strong> PPI.<br />
Finally, chapter 8 gives an overview <strong>of</strong> the results <strong>and</strong> the subsequent<br />
discussion.<br />
41
1.5. REFERENCES<br />
Abduljawad KA, Langley RW, Bradshaw CM, Szabadi E (1997) Effects <strong>of</strong> clonidine <strong>and</strong> diazepam on the<br />
acoustic startle response <strong>and</strong> on its <strong>inhibition</strong> by '<strong>prepulse</strong>s' in man. J Psychopharmacology 11:29-<br />
34<br />
Abduljawad KA, Langley RW, Bradshaw CM, Szabadi E (1999) Effects <strong>of</strong> bromocriptine <strong>and</strong> haloperidol<br />
on <strong>prepulse</strong> <strong>inhibition</strong>: comparison <strong>of</strong> the acoustic startle eyeblink response <strong>and</strong> the N1/P2 <strong>auditory</strong><strong>evoked</strong><br />
response in man. J Psychopharmacology 13:3-9<br />
Adler LE, Pachtman E, Franks RD, Pecevich, Waldo MC, Freedman R (1982) Neurophysiological<br />
evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol<br />
Psychiatry 17:639-653<br />
Adler LE, Waldo MC, Freeman R (1985) Neurophysiologic studies <strong>of</strong> sensory gating in schizophrenia:<br />
comparison <strong>of</strong> <strong>auditory</strong> <strong>and</strong> visual responses. Biol Psychiatry 20:1284-1296<br />
Adler LE, Rose G, Freedman R (1986) Neurophysiological studies <strong>of</strong> sensory gating in rats: effects <strong>of</strong><br />
amphetamine, phencyclidine, <strong>and</strong> haloperidol. Biol Psychiatry 21: 787–798<br />
Adler LE, Pang K, Gerhardt G, Rose GM (1988) Modulation <strong>of</strong> the gating <strong>of</strong> <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong><br />
by norepinephrine: pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry<br />
24:179-190<br />
Adler LE, Waldo MC, Tatcher A, Cawthra E, Baker N, Freedman R (1990) Lack <strong>of</strong> relationship <strong>of</strong><br />
<strong>auditory</strong> gating defects to negative symptoms in schizophrenia. Schizophrenia Res 3:131-138<br />
Adler LE, Waldo MC. (1991) Counterpoint: Sensory <strong>Gating</strong>-Hippocampal Model <strong>of</strong> Schizophrenia.<br />
Schizophr Bull 17:19-24.<br />
Adler LE, Hope C, H<strong>of</strong>fner LD, Stephen C, Young D, Herhardt G (1994) Bromocriptine impairs P50<br />
<strong>auditory</strong> sensory gating in normal control subjects. Biol Psychiatry 35:630<br />
Adler LE, Olincy A, Waldo M, Harris JG, Griffith JG, Stevens K, Flach K, Nagamoto H, Bickford P,<br />
Leonard S, Freedman R (1998) Schizophrenia, sensory gating <strong>and</strong> nicotine receptors. Schizophr Bull<br />
24:189-202.<br />
Aghajanian GK, Marek GJ (2000) Serotonin model <strong>of</strong> schizophrenia: emerging role <strong>of</strong> glutamate<br />
mechanisms. Brain Res Brain Res Rev 31: 302-312<br />
Albin RL, Young AB, Penney JB (1989) The functional anatomy <strong>of</strong> basal ganglia disorders. Trends<br />
Neurosci 12: 366–375<br />
Aldes LD (1988) Thalamic connectivity <strong>of</strong> rat somatic motor cortex. Brain Res Bull 20:333-348<br />
Alex<strong>and</strong>er GE, Crutcher MD (1990) Functional architecture <strong>of</strong> basal ganglia circuits: neural substrates<br />
<strong>of</strong> parallel processing. Trends Neurosci 13: 266-271<br />
Andersen RA, Knight PL, Merzenich MM (1980) The thalamocortical <strong>and</strong> corticothalamic connections <strong>of</strong><br />
AI, AII, <strong>and</strong> the anterior <strong>auditory</strong> field (AAF) in the cat: evidence for two largely segregated systems<br />
<strong>of</strong> connections. J Comp Neurology 194:663-701.<br />
Amalric M, Koob GF (1993) Functionally selective neurochemical afferents <strong>and</strong> efferents <strong>of</strong> the<br />
mesocorticolimbic <strong>and</strong> nigrostriatal dopamine system. Prog Brain Res 99:209-226<br />
Amalric M, Koob GF (1987) Depletion <strong>of</strong> dopamine in the caudate nucleus but not in nucleus<br />
accumbens impairs reaction-time performance in rats. J Neurosc 7:2129-2134<br />
Amaral DG, Witter MP (1995) Chapter 21: Hippocampal formation. In: The rat nervous system,<br />
Paxinos G (Eds) Academic Press, London, UK, pp 443-493<br />
Arts MP, Cools AR (1998) Bilateral 6-hydroxydopamine lesion in the dopaminergic A8 cell group<br />
produces long-lasting deficits in motor programming <strong>of</strong> cats. Behav Neurosci 112:102-115.<br />
Baker N, Adler L, Franks RD, Waldo M, Berry S, Nagamoto H, et al. (1987) Neurophysiological<br />
assessment <strong>of</strong> sensory gating in psychiatric inpatients: Comparison between schizophrenia <strong>and</strong><br />
other diagnoses. Biol Psychiatry 22:603-617<br />
Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong><br />
produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394-8401.<br />
Bakshi VP, Swerdlow NR, Braff DL, Geyer MA (1998) Reversal <strong>of</strong> isolation rearing-induced deficits in<br />
PPI by Seroquel <strong>and</strong> olanzapine. Biol Psychiatry 43:436-445<br />
Bakshi VP, Geyer MA (1999) Ontogeny <strong>of</strong> isolation rearing-induced deficits in sensorimotor gating in<br />
rats. Physiol Behav 67:385-392<br />
Bassareo V, Di Chiara G (1999) Differential responsiveness <strong>of</strong> dopamine transmission to food stimuli<br />
in nucleus accumbens shell/core compartments. Neuroscience 89:637-641<br />
Bardgett ME, Olney JW, Jackson JL, Wrona CT, Csernansky JG (1993) Connecting hippocampal<br />
neuropathy with dopamine dysfunction in schizophrenia: IVC kainic acid as an animal model. Soc<br />
Neurosc Abstr 19:8<br />
Bardgett ME, Jackson JL, Taylor GT, Csernasky JG (1995) Kainic acid decreases hippocampal neuronal<br />
number <strong>and</strong> increase in dopamine receptor binding in the nucleus accumbens: an animal model <strong>of</strong><br />
schizophrenia. Behav Brain Res 70:153-164<br />
Barkley RA (1998) Attention-deficit hyperactivity disorder. Sci Am 279: 66-71<br />
Berendse HW, Groenewegen HJ (1991) Restricted cortical termination fields <strong>of</strong> the midline <strong>and</strong><br />
intralaminar thalamic nuclei in the rat. Neuroscience 42:73-102<br />
Berendse HM, Galis-de-Graaf Y, Groenewegen HJ (1992) Topographic organization <strong>and</strong> relationship<br />
with ventral striatal compartments <strong>of</strong> prefrontal corticostriatal projections in the rat. J Comp Neurol<br />
316:314-347<br />
Berger B, Thierry AM, Tassin JP, Moyne MA (1976) Dopaminergic innervation <strong>of</strong> the rat prefrontal<br />
cortex: a fluorescence histochemical study. Brain Res 106:133-145<br />
42
Bernstein SN, Beninger RJ (2000) Turning in rats following intraaccumbens shell injections <strong>of</strong><br />
amphetamine or eticlopride. Pharmacol Biochem Behav 65:203-207<br />
Bickford-Wimer PC, Nagamoto H, Johnson R, Adler LE, Egan M, Rose GM, Freedman R (1990) Auditory<br />
sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:174-182<br />
Bickford-Wimer P, Nagamoto H, Johnson R, Adler L, Egan M, Rose GM, Freedman R (1990) Sensory<br />
gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:183–192<br />
Bickford PC, Luntz-Leybman V, Freedman R (1993) Auditory sensory gating in the rat HPC: Modulation<br />
by brainstem activity. Brain Res 607:33-38<br />
Björklund A, Lindvall O (1984) Dopamine-containing system in the CNS. In: Björklund A, Hökfelt O<br />
(Eds) Classical transmitters in the CNS, Part I (H<strong>and</strong>book <strong>of</strong> chemical neuroanatomy). Elsevier,<br />
Amsterdam, pp 55-122<br />
Blumenthal TD, Gescheider GA (1987) Modification <strong>of</strong> the acoustic startle reflex by a tactile <strong>prepulse</strong>:<br />
the effects <strong>of</strong> stimulus onset asynchrony <strong>and</strong> <strong>prepulse</strong> intensity. Psychophysiology 24:320-327<br />
Blumenthal TD, Flaten MA (1994) Selective effects <strong>of</strong> attentional direction on the startle reflex at<br />
different stages <strong>of</strong> processing. Psychobiology 22:338-346<br />
Blumenthal TD (1995) PPI <strong>of</strong> the startle eyeblink as an indicator <strong>of</strong> temporal summation.<br />
Percept Psychophys 57:487-494.<br />
Bolam JP, Izzo IN, Graybiel AM (1988) Cellular substrate <strong>of</strong> the histochemically defined<br />
striosome/matrix system <strong>of</strong> the caudate nucleus: A combined Golgi <strong>and</strong> immunocytochemical study<br />
in cat <strong>and</strong> ferret. Neuroscience 24:853–875<br />
Bourdelais A, Kalivas PW (1990) Amphetamine lowers extracellular GABA concentration in the ventral<br />
pallidum. Brain Res 516:132-136<br />
Boutros NN, Torello MW, Barker BA, Tueting PA, Wu SC, Nasrallah HA (1995). The P50 <strong>evoked</strong><br />
potential component <strong>and</strong> mismatch detection in normal volunteers: implications for the study <strong>of</strong><br />
sensory gating. Psychiatry Res 57:83-88<br />
Boutros NN, Bonnet KA, Millana R, Liu J (1997) A parametric study <strong>of</strong> the N40 <strong>auditory</strong> <strong>evoked</strong><br />
potential. Biol Psychiatry 42:1051-1059<br />
Boutros NN, Belger A (1999) Midlatency <strong>evoked</strong> <strong>potentials</strong> attenuation <strong>and</strong> augmentation reflect<br />
different aspects <strong>of</strong> sensory gating. Biol Psychiatry 45:917-922<br />
Boutros NN, Belger A, Campbell D, D'Souza CD, Krystal J (1999) Comparison <strong>of</strong> four components <strong>of</strong><br />
sensory gating in schizophrenia <strong>and</strong> normal subjects: a preliminary report. Psychiatry Res 88:199-<br />
130<br />
Bouyer JJ, Park DH, Joh TH, Pickel VM (1984) Chemical <strong>and</strong> structural analysis <strong>of</strong> the relation between<br />
cortical inputs <strong>and</strong> tyrosine hydroxylase-containing terminals in rat neostriatum. Brain Res<br />
302:267–275<br />
Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Prestimulus effects on human startle<br />
reflex in normals <strong>and</strong> schizophrenics. Psychophysiology 14: 339–343<br />
Braff DL, Grillon C, Geyer MA (1992a) Sensorimotor gating <strong>and</strong> schizophrenia: human <strong>and</strong> animal<br />
model studies. Arch Gen Psychiatry 47:181–188<br />
Braff DL, Grillon C, Geyer MA (1992b) <strong>Gating</strong> <strong>and</strong> habituation <strong>of</strong> the startle reflex in schizophrenic<br />
patients. Arch Gen Psychiatry 49:206-215<br />
Braff DL (1993) Information processing <strong>and</strong> attention dysfunctions in schizophrenia. Schizophr Bull<br />
18:233–259<br />
Braff DL, Swerdlow NR, Geyer MA (1999) Symptom correlates <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> deficits in male<br />
schizophrenic patients. Am J Psychiatry 156:596-602<br />
Breier A (1995) Serotonin, schizophrenia <strong>and</strong> antipsychotic drug action. Schizophr Res 14:187-202<br />
Bristow LJ, L<strong>and</strong>on L, Saywell KL, Tricklebank MD (1995) The glycine/NMDA receptor antagonist, L-<br />
701,324 reverses isolation-induced deficits in PPI in the rat. Psychopharmacology 118:230-232<br />
Bubser M, Koch M (1994) Prepulse <strong>inhibition</strong> <strong>of</strong> the acoustic startle response <strong>of</strong> rats is reduced by 6hydroxydopamine<br />
lesions <strong>of</strong> the medial PFC. Psychopharmacology 113:487-492<br />
Buzsaki G, Laszlovszky I, Lajtha A, Vadasz C (1990) Spike-<strong>and</strong>-wave neocortical patterns in rats:<br />
genetic <strong>and</strong> aminergic control. Neuroscience 38:323-333<br />
Cacace AT, Satya-Murti S, Wolpaw JR (1990) Human middle-latency <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong>:<br />
vertex <strong>and</strong> temporal components. Electroenceph Clin Neurophysiol 77:6-18<br />
Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle <strong>prepulse</strong> <strong>inhibition</strong> <strong>and</strong> habituation in<br />
patients with schizotypal personality disorder. Am J Psychiatry 150:1862-1867.<br />
Cadenhead KS, Swerdlow NR, Shafer K, Diaz M, Braff DL (1999) Modulation <strong>of</strong> the startle response<br />
<strong>and</strong> laterality in schizophrenic patients, their relatives <strong>and</strong> schizotypical personality disorder:<br />
evidence <strong>of</strong> inhibitory deficits. Proc Am Acad Neuropsychopharmacology 136<br />
Cadenhead KS, Light GA, Geyer MA, Braff DL (2000) Sensory gating deficits assessed by the P50<br />
event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry 157:55-59<br />
Caine SB, Geyer MA, Swerdlow NS (1992) Hippocampal modulation <strong>of</strong> acoustic startle response <strong>and</strong><br />
<strong>prepulse</strong> <strong>inhibition</strong> in the rat. Pharmacol Biochem Behav 43: 1201–1208<br />
Caine SB, Geyer MA, Swerdlow NR (1995) Effects <strong>of</strong> D3/D2 dopamine receptor agonists <strong>and</strong><br />
antagonists on PPI <strong>of</strong> acoustic startle in the rat. Neuropsychopharmacology 12:139-145<br />
Calloway E (1973) Habituation <strong>of</strong> averaged <strong>evoked</strong> <strong>potentials</strong> in man. In: HVS Peeke, MJ Herz (Eds).<br />
Habituation. New York: Academic Press, pp 153-174<br />
Campeau S, Davis M (1995) Prepulse <strong>inhibition</strong> <strong>of</strong> the acoustic startle reflex using visual <strong>and</strong> <strong>auditory</strong><br />
<strong>prepulse</strong>s: disruption by apomorphine. Psychopharmacology 117:267-274<br />
Cardenas VA, McCallin K, Hopkin R, Fein G (1997) A comparison <strong>of</strong> the repetitive <strong>and</strong> conditioningtesting<br />
P50 paradigm. Electroenceph Clin Neurophysiol 104:157-164<br />
43
Carlsson A (1988) The current status <strong>of</strong> the dopamine hypothesis <strong>of</strong> schizophrenia.<br />
Neuropsychopharmacology 1:197<br />
Carlsson M, Carlsson A (1990) Interactions between glutamatergic <strong>and</strong> monoaminergic systems within<br />
the basal ganglia: Implications for schizophrenia <strong>and</strong> Parkinson's disease. Trends Neurosci 13: 272-<br />
276<br />
Carpenter MB (1978) Core text <strong>of</strong> neuroanatomy. Williams <strong>and</strong> Wilkins, Baltimore<br />
Carter CJ, Pycock CJ (1980) Behavioral <strong>and</strong> biochemical effects <strong>of</strong> dopamine <strong>and</strong> noradrenaline<br />
depletion within the medial prefrontal cortex <strong>of</strong> the rat. Brain Res 192:163-76<br />
Castellanos FX, Fine EJ, Hallett M (1996) Sensorimotor gating in boys with Tourette’s syndrome <strong>and</strong><br />
ADHD: preliminary results. Biol Psychiatry 39:33-41<br />
Chevalier G, Vacher S, Deniau JM, Desban M (1985) Dis<strong>inhibition</strong> as a basic process in the expression<br />
<strong>of</strong> striatal function I: The striatonigral influence on tecto-spinal/tecto-diencephalic neurons. Brain<br />
Res 334:215–226<br />
Chiappa KH (1983) Evoked <strong>potentials</strong> in clinical medicine. Raven Press, New York<br />
Civelli et al (1993) Molecular diversity <strong>of</strong> the dopamine receptors. Ann Rev Pharmacol Toxicol 32:281<br />
Clementz AR, Geyer MA, Braff DL (1997) P50 suppression among schizophrenia <strong>and</strong> normal<br />
comparison subjects: a methodological analysis. Biol Psychiatry 41: 1035–1044<br />
Coenen AML, Drinkenburg WHIM, Peeters BWMM, Vossen JMH, Van Luijtelaar ELJM (1990) Absence<br />
epilepsy <strong>and</strong> the level <strong>of</strong> vigilance in rats <strong>of</strong> the WAG/Rij strain. Neurosc Biobehav Rev 15:259-263<br />
Coenen AM, Drinkenburg WH, Inoue M, Luijtelaar EL (1992) Genetic models <strong>of</strong> absence epilepsy, with<br />
emphasis on the WAG/Rij strain <strong>of</strong> rats. Epilepsy Res 12:75-86<br />
Cools AR, Van Rossum (1976) Excitation-mediated <strong>and</strong> <strong>inhibition</strong>-mediated dopamine receptors: a<br />
new concept towards a better underst<strong>and</strong>ing <strong>of</strong> electrophysiological, biochemical, pharmacological,<br />
functional <strong>and</strong> clinical data. Psychopharmacologia 45:243-254<br />
Cools AR, Struyker Boudier HAJ, Van Rossum JM (1976) Dopamine receptors: selective agonists <strong>and</strong><br />
antagonists <strong>of</strong> functionally distinct types within the feline brain. Eur J Pharmacol 37:283-293<br />
Cools AR (1977) Two functionally <strong>and</strong> pharmacologically distinct receptors in the rat brain. In Costa E,<br />
Gessa GL (Eds) Advances in biochemical psychopharmacology. New York: Raven Press, pp 215-225<br />
Cools AR, Jaspers R, Schwarz M, Sontag KH, Vrijmoed De Vries M, Van den Bercken J (1984) Basal<br />
ganglia <strong>and</strong> switching motor programs. In: McKenzie JS, Klemm RE, Wilcock LN (Eds). Basal<br />
ganglia: structure <strong>and</strong> function. New York: Plenum Press, pp 513-544<br />
Cools AR, Brachten R, Heeren D, Willemen A, Ellenbroek B (1990) Search after neurobiological pr<strong>of</strong>ile<br />
<strong>of</strong> individual-specific features <strong>of</strong> Wistar rats. Brain Res Bull 24:49-69<br />
Cools AR, Van de Bos R, Ploeger G, Ellenbroek BA (1991) <strong>Gating</strong> function <strong>of</strong> noradrenaline in the<br />
ventral striatum: its role in behavioral responses to environmental <strong>and</strong> pharmacological challenges.<br />
In: Willner P, Scheel-Kruger J (Eds). The mesolimbic DA system: from motivation to action, pp 141-<br />
173<br />
Cools AR, Peeters BW (1992) Differences in spike-wave discharges in two rat selection lines<br />
characterized by opposite dopaminergic activities. Neurosci Lett 134:253-256<br />
Cools AR, de Beltran KK, Prinssen EPM, Koshikawa N (1993) Differential role <strong>of</strong> core <strong>and</strong> shell <strong>of</strong> the<br />
nucleus accumbens in jaw movements <strong>of</strong> rats. Neurosc Res Comm 14:55-61<br />
Cools AR, Miwa Y, Koshikawa N (1995) Role <strong>of</strong> dopamine D1 <strong>and</strong> D2 receptors in the nucleus<br />
accumbens in jaw movements <strong>of</strong> rats: a critical role <strong>of</strong> the shell. Eur J Pharmacology 286:41-47<br />
Cools AR, Ellenbroek BA, Gingras MA, Engbersen A, Heeren D (1997). Differences in vulnerability <strong>and</strong><br />
susceptibility to dexamphetamine in Nijmegen high <strong>and</strong> low responders to novelty: a dose-effect<br />
analysis <strong>of</strong> spatio-temporal programming <strong>of</strong> behaviour. Psychopharmacology 132:181–187<br />
Cools AR, Gingras MA (1998) Nijmegen high <strong>and</strong> low responders to novelty: a new tool in the search<br />
after the neurobiology <strong>of</strong> drug abuse liability. Pharmacol Biochem Behav 60:151-159<br />
Cooper JR, Bloom FE, Roth RH (1991) The Biochemical Basis <strong>of</strong> Neuropharmacology (6th ed.). New<br />
York: Oxford University Press.<br />
Cullum CM, Harris JG, Waldo MC, Smern<strong>of</strong>f E, Madison A, Nagamoto HT, Griffith J, Adler LE, Freedman<br />
R (1993) Neurophysiological <strong>and</strong> neuropsychological evidence for attentional dysfunction in<br />
schizophrenia. Schizophr Res 10:131-141<br />
Davis M, Gendelman D, Tischler M, Geldelman P (1982) A primary acoustic startle circuit: Lesion <strong>and</strong><br />
stimulation studies. J Neurosc 2:791-805.<br />
Decker MW, Curzon P, Brioni JD (1995) Influence <strong>of</strong> separate <strong>and</strong> combined septal <strong>and</strong> amygdala<br />
lesions on memory, acoustic startle, anxiety, <strong>and</strong> locomotor activity in rats. Neurobiol learning<br />
Memory 64:156-168<br />
Deniau JM, Chevalier G (1985) Dis<strong>inhibition</strong> as a basic process in the expression <strong>of</strong> striatal functions<br />
II: The striato-nigral influence on thalamocortical cells <strong>of</strong> the ventromedial thalamic nucleus. Brain<br />
Res 334:227–233<br />
Descarries TW, Lemay B, Doucet G, Berger B (1987) Regional <strong>and</strong> laminar density <strong>of</strong> the dopamine<br />
innervation in adult rat cerebral cortex. Neuroscience 21:807-824<br />
Di Chiara G, Imperato A (1988a) Drugs abused by humans preferentially increase synaptic dopamine<br />
concentrations in the mesolimbic system <strong>of</strong> freely moving rats. Proc Natl Acad Sci 85:5274-5278<br />
Donoghue JP, Herkenham M (1986) Neostriatal projections from individual cortical fields conform to<br />
histochemically distinct striatal compartments in the rat. Brain Res 365:397–403<br />
Drinkenburg WHIM, Coenen AML, Vossen JMH, Van Luijtelaar (1991) Spike-wave discharges <strong>and</strong><br />
sleep-wake states in rats with absence epilepsy. Epilepsy Res 9:218-224<br />
Duffy FH, Iyer VG, Surwillo WW (1989) Clinical Electroencephalography <strong>and</strong> Topographic Brain<br />
Mapping: Technology <strong>and</strong> Practice. Springer-Verlag New York Inc, New York<br />
44
Eccles JC (1969) The Inhibitory Pathways <strong>of</strong> the Central Nervous System. Charles C Thomas Publisher,<br />
Springfield<br />
Ellenbroek BA, Cools AR (1990) Animal models with construct validity for schizophrenia. Behav<br />
Pharmacol 1: 469–490<br />
Ellenbroek BA, Cools AR (1995a) Animal models <strong>of</strong> psychotic disturbances. In: den Boer JA,<br />
Westenberg HGM, van Praag HM (Eds) Advances in the neurobiology <strong>of</strong> schizophrenia. Wiley,<br />
Chichester, pp 89–109<br />
Ellenbroek BA, Cools AR (1995b) Towards an integration <strong>of</strong> animal models <strong>and</strong> clinical concepts <strong>of</strong><br />
schizophrenia. Acta Neuropsychiatry 7:S64–S67<br />
Ellenbroek BA, Geyer MA, Cools AR (1995) The behavior <strong>of</strong> APO-SUS rats in animal models with<br />
construct validity for schizophrenia. J Neurosci 15:7604–7611<br />
Ellenbroek BA, Budde S, Cools AR (1996) Prepulse <strong>inhibition</strong> <strong>and</strong> latent <strong>inhibition</strong>: the role <strong>of</strong><br />
dopamine in the medial prefrontal cortex. Neuroscience 75:535–542<br />
Ellenbroek BA, van den Kroonenberg PT, Cools AR (1998a) The effects <strong>of</strong> an early stressful life event<br />
on sensorimotor gating in adult rats. Schizophr Res 30:251-260<br />
Ellenbroek BA, van Luijtelaar G, Frenken M, Cools AR (1999) Sensory gating in rats: lack <strong>of</strong> correlation<br />
between <strong>auditory</strong> <strong>evoked</strong> potential gating <strong>and</strong> PPI. Schizophr Bull 25:777-788<br />
Ellenbroek BA, Sluyter F, Cools AR (2000) The role <strong>of</strong> genetic <strong>and</strong> early environmental factors in<br />
determining apomorphine susceptibility. Psychopharmacology 148:124-131<br />
Ettenberg A (1989) Dopamine, neuroleptics <strong>and</strong> reinforced behavior. Neurosci Biobehav Rev 13:105-<br />
111<br />
Fallon JH, Loughlin SE MP (1995) Chapter 12: Substantia nigra. In: The rat nervous system, Paxinos G<br />
(Eds) Academic Press, London, UK, pp 215-237.<br />
Fendt M, Koch M (1999) Cholinergic modulation <strong>of</strong> the acoustic startle response in the caudal pontine<br />
reticular nucleus <strong>of</strong> the rat. Eur J Pharmacol 370:101-107<br />
Ferino F, Thierry AM, Saffroy M, Glowinski J (1987) Interhemispheric <strong>and</strong> subcortical collaterals <strong>of</strong><br />
medial prefrontal cortical neurons in the rat. Brain Res 417:257–266<br />
Filion D, Dawson ME, Schell AM (1993) Modification <strong>of</strong> the acoustic startle-reflex eyeblink: a tool for<br />
investigating early <strong>and</strong> late attentional processes. Biol Psychology 35:185-200<br />
Filion D, Dawson ME, Schell AM (1998) The psychological significance <strong>of</strong> human startle eyeblink<br />
modification: a review. Biol Psychology 47:1-43<br />
Flach KA, Gerhardt KA, Adler LE (1995) Interactions between the cholinergic <strong>and</strong> dopaminergic<br />
systems in a computer-model <strong>of</strong> sensory gating in the CA3 neural-network <strong>of</strong> the hippocampus.<br />
Schizophr Res 15: 173-173<br />
Franks RD, Adler LE, Waldo MC, Alpert J, Freedman R (1983) Neurophysiological studies <strong>of</strong> sensory<br />
gating in mania: comparison with schizophrenia. Biol Psychiatry 18:989-1005<br />
Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD (1983) Neurophysiological evidence for a<br />
defect in inhibitory pathways in schizophrenia: Comparison <strong>of</strong> medicated <strong>and</strong> drug-free patients.<br />
Biol Psychiatry 18:537-551<br />
Freedman R, Mirsky AF (1991) Event related <strong>potentials</strong>: exogenous components. In: Steinhauer SR,<br />
Gruzelier JH, Zubin J (Eds) H<strong>and</strong>book <strong>of</strong> schizophrenia, vol 5: neuropsychology, psychophysiology<br />
<strong>and</strong> information processing. Elsevier, Amsterdam, pp 71–90<br />
Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased<br />
numbers <strong>of</strong> hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22-33<br />
Freedman R, Adler LE, Myles-Worsley M, Nagamoto HT, Miller C, Kisley M, McRae K, Waldo M (1996)<br />
Inhibitory gating <strong>of</strong> an <strong>evoked</strong> response to repeated <strong>auditory</strong> stimuli in schizophrenic <strong>and</strong> normal<br />
subjects: human recordings, computer simulation, <strong>and</strong> an animal model. Arch Gen Psychiatry<br />
53:1114-1121<br />
Freund TF, Powell JF, Smith AD (1984) Tyrosine hydroxylase-immunoreactive boutons in synaptic<br />
contact with identified striatonigral neurons with particular reference to dendritic spines.<br />
Neuroscience 13:1189–1215<br />
Fuxe K, Agnati LF, Kalia M, Goldstein M, Andersson K, Härfstr<strong>and</strong> A (1985) Dopaminergic system in<br />
the brain <strong>and</strong> pituitary. In: Fluckiger E, Muller EE, Thorner MO (Eds) The dopaminergic system<br />
(Basic <strong>and</strong> clinical aspects <strong>of</strong> neuroscience). Springer-Verlag, Berlin, pp 11-25<br />
Gelissen M, Cools AR (1988) Effect <strong>of</strong> intracaudate haloperidol <strong>and</strong> apomorphine on switching motor<br />
patterns upon current behavior <strong>of</strong> cats. Brain Res 29:17-26<br />
Gerfen CR (1984) The neostriatal mosaic: Compartmentalization <strong>of</strong> corticostriatal input <strong>and</strong><br />
striatonigral output systems. Nature 311:461–464<br />
Gerfen CR (1985) The neostriatal mosaic: I Compartmental organization <strong>of</strong> projections from the<br />
striatum to the substantia nigra in the rat. J Comp Neurol 236:454–476<br />
Gerfen CR, Herkenham M, Thibault J (1987a) The neostriatal mosaic: II Patch– <strong>and</strong> matrix-directed<br />
mesostriatal dopaminergic <strong>and</strong> non-dopaminergic systems. J Neurosci 7:3915–3934<br />
Gerfen CR, Herkenham M, Thibault J (1987b) The neostriatal mosaic: III Biochemical <strong>and</strong><br />
developmental dissociation <strong>of</strong> patch-matrix mesostriatal systems. J Neurosci 7: 3935-3944<br />
Gerfen CR (1989) The neostriatal mosaic: Striatal patch-matrix organization is related to cortical<br />
lamination. Science 246:385–388<br />
Gerfen CR, Baimbridge KG, Miller JJ (1985) The neostriatal mosaic: Compartmental distribution <strong>of</strong><br />
calcium binding protein <strong>and</strong> parvalbumin in the basal ganglia <strong>of</strong> the rat <strong>and</strong> monkey. Proc Natl Acad<br />
Sci USA 82: 8780–8784.<br />
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, et al (1990) D1 <strong>and</strong> D2 dopamine receptorregulated<br />
gene expression <strong>of</strong> striatonigral <strong>and</strong> striatopallidal neurons. Science 250:1429–1432<br />
45
Gerfen CR (1992a) The neostriatal mosaic: multiple levels <strong>of</strong> compartmental organization. Trends<br />
Neurosci 15:133-139<br />
Gerfen CR (1992b) The neostriatal Mosaic: multiple Levels <strong>of</strong> compartmental organization in the basal<br />
ganglia. Ann Rev Neurosci 15:285–320<br />
Gewirtz JC, Davis M (1995) Habituation <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the startle reflex using an <strong>auditory</strong><br />
<strong>prepulse</strong> close to background noise. Behav Neurosc 109:388-395<br />
Geyer MA, Braff DL, Mansbach RS (1989) Failure <strong>of</strong> haloperidol to block the disruption <strong>of</strong> sensory<br />
motor gating induced by phencyclidine <strong>and</strong> MK801. Biol Psychiatry 25: 169A–170A<br />
Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990) Startle response models <strong>of</strong> sensorimotor<br />
gating <strong>and</strong> habituation deficits in schizophrenia. Brain Res Bull 25: 485–498<br />
Goeders NE, Smith JE (1983) Cortical dopaminergic involvement in cocaine reinforcement. Science<br />
221: 773-5<br />
Gottesman II (1991) Schizophrenia genesis. EH Freeman, New York<br />
Graham FK, Murray GM (1977) Discordant effects <strong>of</strong> weak prestimulation on magnitude <strong>and</strong> latency <strong>of</strong><br />
the blink reflex. Physiol Psychol 5:108-114<br />
Griffith JM, Waldo M, Adler LE, Freedman R (1993) Normalization <strong>of</strong> <strong>auditory</strong> sensory gating in<br />
schizophrenics after a brief period for sleep. Psychiatric Res 49:29-39<br />
Griffith JM, Freedman R (1995) Normalization <strong>of</strong> the <strong>auditory</strong> P50 gating deficit <strong>of</strong> schizophrenic<br />
patients after NREM, but not REM sleep. Psychiatry Res 56:271- 278<br />
Griffith JM, O'Neill JE, Petty F, Garver DL (1996) Effects <strong>of</strong> nicotine <strong>and</strong> stage 2 sleep on <strong>auditory</strong> P50<br />
gating in schizophrenia. [Abstract] Biol Psychiatry 39:652<br />
Groenewegen HJ, Vermeulen-Van de Zee E, Te Kortschot A, Witter (1987) Organization <strong>of</strong> the<br />
projections from the subiculum to the ventral striatum in the rat. A study using anterograde<br />
transport <strong>of</strong> Phaseolus vulgaris leucoagglutinin. Neuroscience 23:103-120<br />
Groenewegen HJ, Berendse HW, Haber SN (1993) Organization <strong>of</strong> the output <strong>of</strong> the ventral pallidal<br />
system in the rat: ventral pallidal efferents. Neuroscience 57:113-142<br />
Groenewegen HJ, Berendse HW (1994) The specificity <strong>of</strong> the non-specific midline <strong>and</strong> intralaminar<br />
thalamic nuclei. Trends Neurosc 17:52-57<br />
Groenewegen HJ, Wright CI, Beijer AVJ (1996) The nucleus accumbens: gateway for limbic structures<br />
to reach the motor system? In: The emotional motor system, G Holstege, R B<strong>and</strong>ler, CB Saper<br />
(Eds) Prog Brain Res 107:485-511<br />
Groenewegen HJ, Galis de Graaf Y, Smeets WJ (1999a) Integration <strong>and</strong> segregation <strong>of</strong> limbic corticostriatal<br />
loops at the thalamic level: an experimental tracing study in rats. J Chem Neuroanatomy<br />
16: 167-185<br />
Groenewegen HJ, Wright CI, Beijer AV, Voorn P (1999b) Convergence <strong>and</strong> segregation <strong>of</strong> ventral<br />
striatal inputs <strong>and</strong> outputs. Ann NY Acad Sci 877: 49-63<br />
Guberman A, Bruni J (1999) Essentials <strong>of</strong> clinical epilepsy. Boston: Butterworth Heinemann<br />
Halgren E, Stapleton J, Smith M, Altafullah I (1986) Generators <strong>of</strong> the human scalp P3s. In: Cracco<br />
RQ, Bodis-Wollner I (Eds). Evoked Potentials. New York: Alan R Liss, pp 269-284<br />
Harrison J B, Woolf N J, Buchwald J S (1990) Cholinergic neurons in the feline pontomesencephalon. I.<br />
Essential role in 'Wave A' generation. Brain Res 520:43-54<br />
Hattori T, McGeer EG, McGeer PL (1978) Fine structural analysis <strong>of</strong> corticostriatal pathway. J Comp<br />
Neurol 185: 347–354<br />
Heimer L. Alheid G (1991) Piecing together the puzzle <strong>of</strong> basal forebrain anatomy. In: TC Napier, P<br />
Kalivas, I Hanin (Eds) The basal forebrain: anatomy to function. Plenum Press, NY, p 1-42<br />
Heimer L, Zahm DS, Alheid GF (1995) Basal ganglia. In: Paxinos G (Eds) The rat nervous system.<br />
Academic Press, San Diego, New York, Boston, London, Sydney, Tokyo, Toronto<br />
Hershman KM, Freedman R, Bickford PC (1995) GABA-B antagonists diminish the inhibitory gating <strong>of</strong><br />
<strong>auditory</strong> response in the rat hippocampus. Neuroscience Letters, 190:133-136<br />
H<strong>of</strong>fman HS, Searle JL (1968) Acoustic <strong>and</strong> temporal factors in the avocation <strong>of</strong> startle. J Acoust Soc<br />
Am 43:269-282<br />
H<strong>of</strong>fman HS, Ison JR (1980) Reflex modification in the domain <strong>of</strong> startle: I. some empirical findings<br />
<strong>and</strong> their implications for how the nervous system processes sensory input. Psychol Rev 87:175-189<br />
H<strong>of</strong>fman DC, Donovan H (1994) D1 <strong>and</strong> D2 dopamine receptor antagonists reverse PPI deficits in an<br />
animal model <strong>of</strong> schizophrenia. Psychopharmacology 115:447-453<br />
Hutchison KE, Swift R (1999) Effect <strong>of</strong> d-amphetamine on PPI <strong>of</strong> the startle reflex in humans.<br />
Psychopharmacology 143:394-400<br />
Ishizuka N, Weber J, Amaral DG (1990) Organization <strong>of</strong> intrahippocampal projections originating from<br />
CA3 pyramidal cells in the rat. J Comp Neurol 295:580-623<br />
Imig TJ, Morel A (1988) Organization <strong>of</strong> the Cat's Auditory Thalamus. In: Auditory Function:<br />
Neurological Bases <strong>of</strong> Hearing. GM Edelman, WE Gall, WM Cowan (Eds), The Neurosciences Institute<br />
(John Wiley & Sons), New York, pp 457-484<br />
Inglis WL, Dunbar JS, Winn P (1994) Outflow from the nucleus accumbens to the pedunculopontine<br />
tegmental nucleus: a dissociation between locomotor activity <strong>and</strong> the acquisition <strong>of</strong> responding for<br />
conditioned reinforcement stimulated by d-amphetamine. Neuroscience 62:51-64<br />
Inoue M, Peeters B, Van Luijtelaar E, Vossen J, Coenen A (1990) Spontaneous occurrence <strong>of</strong> spikewave<br />
discharges in five inbred strains <strong>of</strong> rats. Physiol Behav 48:199-201<br />
Inoue M, Ates N, Vossen JMH, Coenen AML (1994) Effects <strong>of</strong> the neuroleptanalgesic Fentanyl-<br />
Fluanisone (Hypnorm) on spike-wave discharges in epileptic rats. Pharmacol Biochem Behav 48:<br />
547-551<br />
46
Irvine DRF, Jackson GD (1983). Auditory input to neurons in mesencephalic <strong>and</strong> rostral pontine<br />
reticular formation: An electrophysiological <strong>and</strong> horseradish peroxidase study in the cat. J<br />
Neurophys 49:1319-1333<br />
Ison JR, Hammond GR, Krauer EE (1973) Effects <strong>of</strong> experience on stimulus-produced reflex-<strong>inhibition</strong><br />
in the rat. Physiol behav 83:324-336<br />
Ison JR, Ashkinazi B (1980) Effects <strong>of</strong> a warning stimulus on reflex elicitation <strong>and</strong> reflex <strong>inhibition</strong>.<br />
Psychophysiology 17:586-591<br />
Ison JR, Sanes JN, Foss JA, Pinckney LA (1990) Facilitation <strong>and</strong> <strong>inhibition</strong> <strong>of</strong> the human startle blink<br />
reflexes by stimulus anticipation. Behav Neurosci 104:418–429<br />
Jaber M, Robinson SW, Missale C, Caron MG (1996) Dopamine receptors <strong>and</strong> brain function.<br />
Neuropharmacology 35:1503-19<br />
Jackson DM, Anden NE, Dahlstrom A (1975a) A functional effect <strong>of</strong> dopamine in the nucleus<br />
accumbens <strong>and</strong> in some other dopamine-rich parts <strong>of</strong> the rat brain. Psychopharmacologia 45:139-<br />
49<br />
Jackson DM, Anden NE, Engel J, Liljequist S (1975b) The effect <strong>of</strong> long-term penfluridol treatment on<br />
the sensitivity <strong>of</strong> the dopamine receptors in the nucleus accumbens <strong>and</strong> in the corpus striatum.<br />
Psychopharmacologia 45:151-155<br />
Jackson DM, Westlund-Danielsson A (1994) Dopamine receptors: molecular biology biochemistry <strong>and</strong><br />
behavioral aspects. Pharmacol Ther 64:291-369<br />
Jarvie <strong>and</strong> Caron (1993) Heterogeneity <strong>of</strong> dopamine receptors. Adv Neurol 60:325<br />
Japha K, Koch M (1999) Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats:<br />
reversal by haloperidol. Psychopharmacology 144:347-354<br />
Jaspers R, Swarz M, Sontag KH, Cools AR (1984) Caudate nucleus <strong>and</strong> programming behavior in cats:<br />
role <strong>of</strong> dopamine in switching motor patterns. Behav Brain Res 14:17-28<br />
Jaspers RM, De Vries TJ, Cools AR (1990) Effects <strong>of</strong> intrastriatal apomorphine on changes in switching<br />
behavior induced by the glutamate agonist AMPA injected into the cat caudate nucleus. Behav Brain<br />
Res 37:247-254<br />
Jennings PD, Schell AM, Filion D, Dawson ME (1996) Tracking early <strong>and</strong> late stages <strong>of</strong> information<br />
processing: contributions <strong>of</strong> startle eyeblink reflex modification. Psychophysiology 33:148-155<br />
Jimenez-Castellanos J, Graybiel AM (1987) Subdivisions <strong>of</strong> the dopamine-containing A8-A9-A10<br />
complex identified by their differential mesostriatal innervation <strong>of</strong> striosomes <strong>and</strong> extrastriosomal<br />
matrix. Neuroscience 23: 223–242<br />
Jimenez-Castellanos J, Graybiel AM (1989) Compartmental origins <strong>of</strong> striatal efferent projections in<br />
the cat. Neuroscience 32: 297–321<br />
Jin Y, Potkin SG, Patterson JV, S<strong>and</strong>man CA, Hetrick WP, Bunney WE Jr (1997) Effects <strong>of</strong> P50<br />
temporal variability on sensory gating in schizophrenia. Psychiatry Res 70:71-81<br />
Jin Y, Bunney WE Jr, S<strong>and</strong>man CA, Patterson JV, Fleming K, Moenter JR, Kalali AH, Hetrick WP, Potkin<br />
SG (1998) Is P50 suppression a measure <strong>of</strong> sensory gating in schizophrenia? Biol Psychiatry<br />
43:873-878<br />
Johansson C, Jackson DM, Svensson L (1994) The atypical antipsychotic, remoxipride, blocks<br />
phencyclidine-induced disruption <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> in the rat. Psychopharmacology 116:37–442<br />
Johansson C, Jackson DM, Zhang J, Svensson L (1995) Prepulse <strong>inhibition</strong> <strong>of</strong> acoustic startle, a<br />
measure <strong>of</strong> sensorimotor gating: effects <strong>of</strong> antipsychotics <strong>and</strong> other agents in rats. Pharmacol<br />
Biochem Behav 52:649–654<br />
Johnson RG, Stevens KE, Rose GM (1998) 5-Hydroxytryptamine2 receptors modulate <strong>auditory</strong> filtering<br />
in the rat. J Pharmacol Exp Ther 285:643-650<br />
Jones E G (1985) The Thalamus. Plenum Press, New York<br />
Jones CK, Shannon HE (2000) Effects <strong>of</strong> scopolamine in comparison with apomorphine <strong>and</strong><br />
phencyclidine on <strong>prepulse</strong> <strong>inhibition</strong> in rats. Eur J Pharmacol 391:105-112<br />
Jongen-Relo AL, Groenewegen HJ, Voorn O (1993) Evidence for a compartmental histochemical<br />
organization <strong>of</strong> the nucleus accumbens in the rat. J Comp Neurol 337:267-276<br />
Judd LL, McAdams L, Budnick B, Braff DL (1992) Sensory gating deficits in schizophrenia: New results.<br />
Am J Psychiatry 149:488-493<br />
Kalat JW (1995) Biological Psychology, 5 th edition, pp 564-579<br />
Karson CN, Garcia-Rill E, Biedermann J, Mrak RE, Husain MM, Skinner RD (1991) The brainstem<br />
reticular formation in schizophrenia. Psychiatry Res 40:31-48<br />
Karper LP, Freeman GK, Grillon C, Morgan CA, Charney DS, Krystal JH (1996) Preliminary evidence <strong>of</strong><br />
an association between sensorimotor gating <strong>and</strong> distractibility in psychosis. J Neuropsychiatry Clin<br />
Neurosc 8:60-66<br />
Kawaguchi Y, Wilson CJ, Emson P (1990) Projection subtypes <strong>of</strong> rat neostriatal matrix cells revealed<br />
by intracellular injection <strong>of</strong> biocytin. J Neurosci 10:3421–3438<br />
Keith VA, Mansbach RS, Geyer MA (1991) Failure <strong>of</strong> haloperidol to block the effects <strong>of</strong> phencyclidine<br />
<strong>and</strong> dizocilpine on <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> startle. Biol Psychiatry 30:557–566<br />
Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine <strong>and</strong> apomorphine responses in the rat<br />
following 6-OHDA lesions <strong>of</strong> the accumbens septi <strong>and</strong> corpus striatum. Brain Res 94:507-522<br />
Kelly JP (1991) Chapter 32: Hearing In: K<strong>and</strong>el ER, Schwarz JH, Jessell TM (Eds) Principles <strong>of</strong> neural<br />
science. Prentice Hall International, London, UK, pp 481-499<br />
Kita H, Chang HT, Kitai ST (1983) Pallidal inputs to subthalamus: Intracellular analysis. Brain Res<br />
264:255–265<br />
Kita H, Kitai ST (1987a) Efferent projections <strong>of</strong> the subthalamic nucleus in the rat: Light <strong>and</strong> electron<br />
microscopic analysis with the PHA-L method. J Comp Neurol 260:435–452<br />
47
Kita H, Kitai ST (1987b) Subthalamic inputs to the globus pallidus <strong>and</strong> the substantia nigra in the rat:<br />
Light <strong>and</strong> electron microscopic studies using PHA-L methods. J Comp Neurol 260:435–452<br />
Kitamura M, koshikawa N, Yoneshige N, Cools AR (1999) Behavioral <strong>and</strong> neurochemical effects <strong>of</strong><br />
cholinergic <strong>and</strong> dopaminergic agonists administered into the accumbal core <strong>and</strong> shell in rats.<br />
Neuropharmacology 38:1397-1407<br />
Kiyatkin EA (1995) Functional significance <strong>of</strong> mesolimbic dopamine. Neurosci Biobehav Rev 19:573-<br />
598<br />
Koch M, Bubser M (1994) Deficient sensorimotor gating after 6-hydroxydopamine lesions <strong>of</strong> the rat<br />
medial prefrontal cortex is reversed by haloperidol. Eur J Neurosci 6:1837-1845<br />
Koch M (1996) The septo-hippocampal system is involved in <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the acoustic startle<br />
response in rats. Behav Neurosci 110:468–493<br />
Koch M, Schnitzler H U (1997) The acoustic startle response in rats: circuits mediating evocation,<br />
<strong>inhibition</strong> <strong>and</strong> potentiation. Behav Brain Res 89:35–49<br />
Koch M (1999) The neurobiology <strong>of</strong> startle. Prog in Neurobiology 59:107-128<br />
Kodsi MH, Swerdlow NR (1994) Quinolinic acid lesions <strong>of</strong> the ventral striatum reduce sensorimotor<br />
gating <strong>of</strong> acoustic startle in rats. Brain Res 643:59-65<br />
Kodsi MH, Swerdlow NR (1995) Prepulse <strong>inhibition</strong> in the rat is regulated by ventral <strong>and</strong> caudodorsal<br />
striato-pallidal circuitry. Behav Neurocience 109:912-928<br />
Kodsi MH, Swerdlow NR (1997) Regulation <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> by ventral pallidal projections Brain<br />
Res Bull 43:219-228<br />
Koester J (1991) Voltage-geared channels <strong>and</strong> the generation <strong>of</strong> the action potential. In: K<strong>and</strong>el ER,<br />
Schwartz JH, Jessell TM (Eds) Principles <strong>of</strong> Neural Science. Elsevier Science Publishers, New York,<br />
pp 104-118<br />
Kolb B, Whishaw Q (1990) Fundamentals <strong>of</strong> human neuropsychology, Chapter 6: The neurological<br />
exam <strong>and</strong> clinical tests. Freeman <strong>and</strong> Company, New York, pp 115-129<br />
Koshikawa N, Yoshida Y, Kitamura M, Saigusa T, Kobayashi M, Cools AR (1996) Stimulation <strong>of</strong><br />
acetylcholine or dopamine receptors in the nucleus accumbens differentially alters dopamine release<br />
in the striatum <strong>of</strong> freely moving rats. Eur J Pharmacol 303:13-19<br />
Kumari V, Checkley SA, Gray JA (1996) Effect <strong>of</strong> cigarette smoking on PPI <strong>of</strong> the acoustic startle reflex<br />
in healthy male smokers. Psychopharmacology 128:54-60<br />
Kumari V, Gray JA (1999) Smoking withdrawal, nicotine dependence <strong>and</strong> PPI <strong>of</strong> the acoustic startle<br />
reflex. Psychopharmacology 141:11-15<br />
Kumari V, Soni W, Sharma T (1999) Normalization <strong>of</strong> information processing deficits in schizophrenia<br />
with clozapine. Am J Psychiatry 156:1046-1051<br />
Lamberti JS, Schwarzkopf SB, Boutros N, Crilly JF, Martin R (1993) Within-session changes in sensory<br />
gating assessed by P50 <strong>evoked</strong> <strong>potentials</strong> in normal subjects. Prog Neuropsychopharmacol Biol<br />
Psychiatry 17:781-791<br />
Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional <strong>and</strong> regulatory roles.<br />
Physiol Rev 71:155-233<br />
Leitner DS, Cohen ME (1985) Role <strong>of</strong> the inferior colliculus in the <strong>inhibition</strong> <strong>of</strong> acoustic startle in the<br />
rat. Physiol Behav 34:65-70<br />
Lennartz RC, Weinberger NM (1992) Frequency selectivity is related to temporal processing in parallel<br />
thalamocortical <strong>auditory</strong> pathways. Brain Res 583:81-92.<br />
Light GA, Malaspina D, Geyer MA, Luber BM, Coleman EA, Sackeim HA, Braff DL (1999) Amphetamine<br />
disrupts P50 suppression in normal subjects. Biol Psychiatry 46:990-996<br />
Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL (2000) Normal P50 suppression in<br />
schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 157:767-<br />
771.<br />
Light GA, Braff DL (2000) Do self-reports <strong>of</strong> perceptual anomalies reflect gating deficits in<br />
schizophrenia patients? Biol Psychiatry 47:463-467<br />
Logue SF, Owen EH, Rasmussen DL, Wehner JM (1997) Assessment <strong>of</strong> locomotor activity, acoustic<br />
<strong>and</strong> tactile startle, <strong>and</strong> PPI <strong>of</strong> startle in inbred mouse strains <strong>and</strong> F1 hybrids: implications <strong>of</strong> genetic<br />
background for single gene <strong>and</strong> quantitative trait loci analyses. Neuroscience 80:1075-1086<br />
Luntz-Leybman V, Bickford PC, Freedman R (1992) Cholinergic gating <strong>of</strong> response to <strong>auditory</strong> stimuli<br />
in rat hippocampus. Brain Res 587:130-136<br />
Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in<br />
the rat. Psychopharmacology 94: 507–514<br />
Mansbach RS (1991) Effects <strong>of</strong> NMDA receptor lig<strong>and</strong>s on sensorimotor gating in the rat. Eur J<br />
Pharmacol 202:61–66<br />
Mansbach RS, Geyer MA (1991) Parametric determinants in prestimulus modification <strong>of</strong> acoustic<br />
startle: interaction with ketamine. Psychopharmacology 105:162–168<br />
Mansbach RS, Brooks EW, Sanner MA, Zorn SH (1998) Selective dopamine D4 receptor antagonists<br />
reverse apomorphine-induced blockade <strong>of</strong> PPI. Psychopharmacology 135:194-200<br />
McGhie A, Chapman J (1961) Disorders <strong>of</strong> attention <strong>and</strong> perception in early schizophrenia. Br J Med<br />
Psychol 34:103–116<br />
Mednick SA, Machon RA, Huttunen MO, Bonnett D (1988) Adult schizophrenia following prenatal<br />
exposure to an influenza epidemic. Arch Gen Psychiatry 45:189-192<br />
Meridith GE, Pattiselanno A, Groenewegen HJ, Haber SN (1996) Shell <strong>and</strong> core in monkey <strong>and</strong> human<br />
nucleus accumbens identified with antibodies to calbindin-D28k. J Comp Neurol 365:628-639<br />
Metrakos JD, Metrakos K (1970) Genetic factors in epilepsy. In: Niedermeyer E (Eds) Modern<br />
Problems Pharmacopsychiatry 4:71-86<br />
48
Miller CL, Bickford PC, Luntz-Leybman V, Adler LE, Gerhardt GA, Freedman R (1992) Phencyclidine<br />
<strong>and</strong> <strong>auditory</strong> sensory gating in the hippocampus <strong>of</strong> the rat. Neuropharmacology 31:1041-1048<br />
Miller CL, Freedman R (1995) The activity <strong>of</strong> hippocampal interneurons <strong>and</strong> pyramidal cells during the<br />
response <strong>of</strong> the HPC to repeated <strong>auditory</strong> stimuli. Neuroscience 69: 371–381<br />
Miyazato H, Skinner RD, Reese NB, Mukawa J, Garcia-Rill E (1996) Midlatency <strong>auditory</strong> <strong>evoked</strong><br />
<strong>potentials</strong> <strong>and</strong> the startle response in the rat. Neuroscience 75: 289–300<br />
Mogenson GJ (1987) Limbic-motor integration. Prog Psychobiol Physiol Psychol, pp 117-170<br />
Morton N, Ellis C, Gray NS, Toone BK, Leigh PN, Chaudhuri KR (1995) The effects <strong>of</strong> apomorphine <strong>and</strong><br />
L-dopa challenge on <strong>prepulse</strong> <strong>inhibition</strong> in patients with Parkinson's disease. Schizophr Res 15:181-<br />
182<br />
Moxon KA, Gerhardt GA, Bickford PC, Austin K, Rose GM, Woodward DJ, Adler LE (1999) Multiple<br />
single units <strong>and</strong> population responses during inhibitory gating <strong>of</strong> hippocampal <strong>auditory</strong> response in<br />
freely-moving rats. Brain Res 825:75-85.<br />
Naatanen R, Picton T (1987) The N1 wave <strong>of</strong> the human electric <strong>and</strong> magnetic response to sound: a<br />
review <strong>and</strong> an analysis <strong>of</strong> the component structure. Psychophysiology 41:585-601<br />
Naber G, Kathman N, Engel RR (1992). P50 suppression in normal subjects: influence <strong>of</strong> stimulus<br />
intensity, test repetition, <strong>and</strong> presentation mode. J Psychophysiol 6:47-53<br />
Nagamine M, Tomisawa K (1999b) A selective dopamine D4 receptor antagonist, NRA0160: a<br />
preclinical neuropharmacological pr<strong>of</strong>ile. Life Sci 65:2109-2125<br />
Nagamoto HT, Adler LE, Waldo MC, Freedman R (1989) Sensory gating in schizophrenics <strong>and</strong> normal<br />
controls: effects <strong>of</strong> changing stimulation interval. Biol Psychiatry 25:549-561.<br />
Nagamoto HT, Adler LE, Waldo MC, Griffith J, Freedman R (1991) <strong>Gating</strong> <strong>of</strong> <strong>auditory</strong> response in<br />
schizophrenics <strong>and</strong> normal controls: Effects <strong>of</strong> recording site <strong>and</strong> stimulation interval on the P50<br />
wave. Schizophr Research 4:31-40<br />
Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R (1996) <strong>Gating</strong> <strong>of</strong> <strong>auditory</strong> P50 in<br />
schizophrenics: Unique effects <strong>of</strong> clozapine. Biol Psychiatry 40:181-188<br />
Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, Hea R, Griffith J (1999) Auditory<br />
P50 in schizophrenics on clozapine: improved gating parallels clinical improvement <strong>and</strong> changes in<br />
plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology 39:10-17<br />
Nakanishi H, Kita H, Kitai ST (1988) An N-methyl-D-aspartate receptor mediated excitatory<br />
postsynaptic potential <strong>evoked</strong> in subthalamic neurons in an in vitro slice preparation in the rat.<br />
Neurosci Lett 95:130–136<br />
Nehlig A (1999) Does caffeine lead to psychological dependence? Chemtech 29:30-35<br />
Nuechterlein KH, Dawson ME (1994). Chapter 117. Neurophysiological <strong>and</strong> psychophysiological<br />
approaches to schizophrenia <strong>and</strong> its pathogenesis. In: Psychopharmacology: the Fourth generation<br />
<strong>of</strong> progress. FE Bloom, DJ Kupfer, BS Bunney, RD Ciaranello, KL Davis, GF Koob, HY Meltzer, CR<br />
Schuster, RI Shader, SJ Watson (Eds). Lippincott, Williams & Wilkins, USA<br />
Newman DB, Ginsberg CY (1994). Reticular nuclei that project to the thalamus in rats: A retrograde<br />
tracer study. Brain Behav Evol 44:1-39.<br />
Oades RD (1985) The role <strong>of</strong> noradrenaline in tuning <strong>and</strong> dopamine in switching between signals in<br />
the CNS. Neurosc Biobehav Rev 8:261-282<br />
Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Kumagai T, Nakazato A, Nagamine M,<br />
Yamaguchi K, Tomisawa K (1999a) The atypical antipsychotic pr<strong>of</strong>ile <strong>of</strong> NRA0045, a novel dopamine<br />
D4 <strong>and</strong> 5-hydroxytryptamine2A receptor antagonist, in rats. Br J Pharmacol 121:515-525<br />
Okuyama S, Kawashima N, Chaki S, Yoshikawa R, Funakoshi T, Ogawa SI, Suzuki Y, Ikeda Y;<br />
Kumagai T, Nakazato A, Ott DA, M<strong>and</strong>el RJ (1995) Amphetamine sensitivity in open-field activity vs.<br />
the PPI paradigm. Brain Res Bull 37:219-222<br />
Patterson JV, Jin Y, Gierczak M, Hetrick WP, Potkin S, Bunney WE, S<strong>and</strong>man CA (2000) Effects <strong>of</strong><br />
temporal variability on P50 <strong>and</strong> the gating ratio in schizophrenia. Arch Gen Psychiatry 57:64<br />
Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press Ltd, London<br />
Paylor R, Crawley JN (1997) Inbred strain differences in PPI <strong>of</strong> the mouse startle response.<br />
Psychopharmacology 132:169-180<br />
Peng RY, Mansbach RS, Braff DL, Geyer MA (1990) A D2 dopamine receptor agonist disrupts<br />
sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia.<br />
Neuropsychopharmacology 3: 211-218<br />
Perry W, Braff DL (1994) Information processing deficits <strong>and</strong> thought disorder in schizophrenia. Am J<br />
Psychiatry 151:363-367<br />
Perry W, Geyer MA, Braff DL (1999) Sensorimotor gating <strong>and</strong> thought disturbance measured in close<br />
temporal proximity in schizophrenic patients. Arch Gen Psychiatry 56:277-281<br />
Peeters BWMM, Van Rijn CM, Vossen JMH, Coenen AML (1989a) Effects <strong>of</strong> GABA-ergic agents on<br />
spontaneous non-convulsive epilepsy, EEG <strong>and</strong> behavior in the WAG/Rij inbred strain <strong>of</strong> rats. Life<br />
Sci 45: 1171-1176<br />
Peeters BWMM, Van Rijn, Van Luijtelaar ELJM, Coenen AML (1989b) Antiepileptic <strong>and</strong> behavioral<br />
actions <strong>of</strong> MK-801 in animal model <strong>of</strong> spontaneous absence epilepsy. Epilepsy Res 3:178-181<br />
Peeters BWMM, Kerbusch JML, Van Luijtelaar ELJM, Vossen JMH, Coenen AML (1990a) Genetics <strong>of</strong><br />
absence epilepsy in rats. Behav Genetics 20:453-262<br />
Peeters BWMM, Van Rijn CM, Vossen JHM, Coenen AML (1990b) Involvement <strong>of</strong> NMDA receptors in<br />
non-convulsive epilepsy in WAG/Rij rats. Life Sci 47:523-529<br />
Pickar D, Litman RE, Konicki PE, Wolkowitz OM, Breier A (1990) Neurochemical <strong>and</strong> neural<br />
mechanisms <strong>of</strong> positive <strong>and</strong> negative symptoms in schizophrenia. Modern Problems<br />
Pharmacopsychiatry 24:124-151<br />
49
Pickles J O (1981) An introduction to the physiology <strong>of</strong> hearing. New York: Harcourt Brace Jovanovich.<br />
Pijnenburg AJ, Van Rossum JM (1973) Letter: Stimulation <strong>of</strong> locomotor activity following injection <strong>of</strong><br />
dopamine into the nucleus accumbens. J Pharmacol 25:1003-1005<br />
Pijnenburg AJ, Honig WM, Boudier HA, Cools AR, Van der Heyden JA, Van Rossum (1976) Further<br />
investigation on the effects <strong>of</strong> ergometrine <strong>and</strong> other ergot derivates following injection into the<br />
nucleus accumbens in the rat. Arch Int Pharmacodyn Ther 222:103-115<br />
Pontieri FE, T<strong>and</strong>a G, Di Chiara G (1995) Intravenous cocaine, morphine, <strong>and</strong> amphetamine<br />
preferentially increase extracellular dopamine in the shell as compared with the core <strong>of</strong> the rat<br />
nucleus accumbens. Proc Natl Acad Sci USA 92:12304-12308<br />
Powell EW, Hatton JB (1969). Projections <strong>of</strong> the inferior colliculus in the cat. J Comp Neurol 136:183-<br />
192<br />
Prinssen EPM, Balestra, Bemelmans FFJ, Cools AR (1994) Evidence for a role <strong>of</strong> the shell <strong>of</strong> the<br />
nucleus accumbens in oral behavior <strong>of</strong> freely moving rats. J Neuroscience 14:1555-1562<br />
Pulvirenti L, Swerdlow NR, Hubner CB, Koob GF (1991) The role <strong>of</strong> limbic-pallidal circuitry in the<br />
activating <strong>and</strong> reinforcing properties <strong>of</strong> psychostimulant drugs. In: Willner P, Scheel-Krüger J (Eds)<br />
The mesolimbic dopamine system: from motivation to action. John Wiley & Sons, New York, pp 131-<br />
140<br />
Ralph RJ, Varty GB, Kelly MA, Wang YM, Caron MG, Rubinstein M, Gr<strong>and</strong>y DK, Low MJ, Geyer MA<br />
(1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption <strong>of</strong><br />
<strong>prepulse</strong> <strong>inhibition</strong> produced by amphetamine in mice. J Neurosci 19:4627-4633.<br />
Reijmers LGJE, Peeters BWMM (1994a) Acoustic <strong>prepulse</strong>s can facilitate the startle reflex in rats:<br />
discrepancy between rat <strong>and</strong> human data resolved. Brain Res Bull 35:337–338<br />
Reijmers LGJE, Peeters BWMM (1994b) Effects <strong>of</strong> acoustic <strong>prepulse</strong>s on the startle reflex in rats: a<br />
parametric analysis. Brain Res 667: 143–159<br />
Reijmers LGJE, V<strong>and</strong>erheyden PML, Peeters BWMM (1995) Changes in <strong>prepulse</strong> <strong>inhibition</strong> after local<br />
administration <strong>of</strong> NMDA receptor lig<strong>and</strong>s in the core region <strong>of</strong> the rat nucleus accumbens. Eur J<br />
Pharmacol 272: 131–138<br />
Reite M, Teale P, Zimmerman J, Davis K, Whalen J (1988) Source location <strong>of</strong> a 50 msec latency<br />
<strong>auditory</strong> <strong>evoked</strong> field component. Electroenceph Clin Neurophysiol 70:490-498<br />
Rigdon GC (1990) Differential effects <strong>of</strong> apomorphine on PPI <strong>of</strong> acoustic startle reflex in two rat<br />
strains. Psychopharmacology 102:419-421<br />
Rigdon GC, Weatherspoon JK (1992) 5-Hydroxytryptamine 1A receptor agonists block <strong>prepulse</strong><br />
<strong>inhibition</strong> <strong>of</strong> the acoustic startle response. J Pharmacol Exp Ther 263:486-493<br />
Roozendaal B, Cools AR (1994) Influence <strong>of</strong> the noradrenergic state <strong>of</strong> the nucleus accumbens in<br />
basolateral amygdala mediated changes in neophobia <strong>of</strong> rats. Behav Neurosci 108:1107-1118.<br />
Rots NY, Cools AR, Berod A, Voorn P, Rostene W, de Kloet ER (1996) Rats bred for enhanced<br />
apomorphine susceptibility have elevated tyrosine hydroxylase mRNA <strong>and</strong> dopamine D2-receptor<br />
binding sites in nigrostriatal <strong>and</strong> tuberoinfundibular dopamine systems. Brain Res 710:189-196<br />
Schaefer GJ, Michael RP (1987) Ethanol <strong>and</strong> current thresholds for brain self-stimulation in the lateral<br />
hypothalamus <strong>of</strong> the rat. Alcohol 4: 209-213<br />
Schwarzkopf SB, Mitra T, Bruno JP (1992) Sensory gating in rats depleted <strong>of</strong> DA as neonates:<br />
potential relevance to findings in schizophrenic patients. Biol Psychiatry 31:759-773<br />
Schwarzkopf SB, Lamberti JS, Smith DA (1993a) Concurrent assessment <strong>of</strong> acoustic startle <strong>and</strong><br />
<strong>auditory</strong> P50 <strong>evoked</strong> potential measures <strong>of</strong> sensory <strong>inhibition</strong>. Biol Psychiatry 33:815–828<br />
Schwarzkopf SB, Bruno JP, Mitra T (1993b) Effects <strong>of</strong> haloperidol <strong>and</strong> SCH 23390 on acoustic startle<br />
<strong>and</strong> PPI under basal <strong>and</strong> stimulated conditions. Prog Neuropsychopharmacol Biol Psychiatry<br />
17:1023-1036<br />
Schwarzkopf SB, McCoy L, Smith DA, Boutros NN (1993c) Test-retest reliability <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong><br />
<strong>of</strong> the acoustic startle response. Biol Psychiatry 34:896-900<br />
Sibley <strong>and</strong> Monsma (1992) Molecular biology <strong>of</strong> dopamine receptors. TIPS 13:61<br />
Siegel C, Waldo M, Mizner G, Adler LE, Freedman R (1984) Deficits in sensory gating in schizophrenic<br />
patients <strong>and</strong> their relatives. Arch Gen Psychiatry 41:607-612<br />
Sills TL (1999) Amphetamine dose dependently disrupts PPI <strong>of</strong> the acoustic startle response in rats<br />
within a narrow time window. Brain Res Bull 48:445-448<br />
Simpson G V, Knight R T (1993) Multiple brain systems generating the rat <strong>auditory</strong> <strong>evoked</strong> potential.<br />
II. Dissociation <strong>of</strong> <strong>auditory</strong> cortex <strong>and</strong> non-lemniscal generator systems. Brain Res 602:251-263<br />
Sipes TA, Geyer MA (1994) Multiple serotonin receptor subtypes modulate <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the<br />
startle response in rats. Neuropharmacology 33:441-448<br />
Sipes TE, Geyer MA (1997) DOI disrupts <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> startle in rats via 5-HT2A receptors in<br />
the ventral pallidum. Brain Res 761:97-104.<br />
Smith Y, Bolam JP, Krosigk MV (1990) Topographical <strong>and</strong> synaptic organization <strong>of</strong> the GABAcontaining<br />
pallidosubthalamic projection in the rat. Eur J Neurosci 2: 500–511<br />
Snyder SH (1976) The dopamine hypothesis <strong>of</strong> schizophrenia: focus on the dopamine receptor. Am J<br />
Psychiatry, 133:197-202<br />
Somogyi P, Bolam JP, Totterdell S, Smith AD (1981) Monosynaptic input from the nucleus accumbensventral<br />
striatum region to retrogradely labeled nigrostriatal neurons. Brain Res 217:245-263<br />
Somogyi P, Bolam JP, Smith AD (1981) Monosynaptic cortical input <strong>and</strong> local axon collaterals <strong>of</strong><br />
identified striatonigral neurons. A light <strong>and</strong> electron microscopic study using the Goldi-peroxidasedegeneration<br />
procedure. J Comp Neurol 195: 567–584<br />
50
Squires NK, Ollo C (1986) Human <strong>evoked</strong> potential techniques: possible appications to<br />
neuropsychology. In: HJ Hannay (Eds) Experimental Techniques in Human Neuropsychology. Oxford<br />
University Press, New York<br />
Starr A, Aguinaldo T, Roe HJ, Michalewski HJ (1997) Sequential changes <strong>of</strong> <strong>auditory</strong> processing during<br />
target detection: Motor responding versus mental counting. Electroenceph Clin Neurophysiol<br />
105:201-212<br />
Steiner H, kitai ST (2000) Regulation <strong>of</strong> rat cortex function by D1 dopamine receptors in the striatum.<br />
J Neurosci 20:5449-5460<br />
Steriade M, Llinas RR (1988) The functional states <strong>of</strong> the thalamus <strong>and</strong> the associated neuronal<br />
interplay. Physiol Rev 68:649-742<br />
Stevens KE, Fuller LL, Rose GM (1991) Dopaminergic <strong>and</strong> noradrenergic modulation on amphetamineinduced<br />
changes in <strong>auditory</strong> gating. Brain Res 555:91–98<br />
Stevens KE, Luthman J, Lindqvist EVA, Johnson RG, Rose GM (1996) Effects <strong>of</strong> neonatal dopamine<br />
depletion on sensory <strong>inhibition</strong> in the rat. Pharmacol Biochem Behav 53:817–823<br />
Stevens KE, Johnson RG, Rose GM (1997) Rats reared in social isolation show schizophrenia-like<br />
changes in <strong>auditory</strong> gating. Pharmacol Biochem Behav 58:1031-1036<br />
Stevens KE, Wear KD (1997) Normalizing effects <strong>of</strong> nicotine <strong>and</strong> a novel nicotinic agonist on<br />
hippocampal <strong>auditory</strong> gating in two animal models. Pharmacol Biochem Behav 57:869-874<br />
Stevens KE, Nagamoto H, Johnson RG, Adams CE, Rose GM (1998) Conic acid lesions in adult rats as<br />
a model <strong>of</strong> schizophrenia: changes in <strong>auditory</strong> information processing. Neuroscience 82: 701–708<br />
Strange (1996) Dopamine receptors: studies on their structure <strong>and</strong> function. Adv Drug Res 28:315<br />
Swanson LW (1982) The projections <strong>of</strong> the ventral tegmental area <strong>and</strong> adjacent regions: A combined<br />
fluorescent retrograde tracer <strong>and</strong> immun<strong>of</strong>luorescence study in the rat. Brain Res Bull 9:321-353<br />
Swerdlow NR, Vaccarino F, Amalric M, Koob G (1986) Neural substrates for the motor-activating<br />
properties <strong>of</strong> psychostimulants: a review <strong>of</strong> recent findings. Pharmacol Biochem Behav 25:233-248<br />
Swerdlow NR, Koob GF (1987) Dopamine, schizophrenia, mania, <strong>and</strong> depression: Toward a unified<br />
hypothesis <strong>of</strong> cortico-striato-pallido-thalamic function. Behav Brain Science 10:197-245<br />
Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990a) Amphetamine<br />
disruption <strong>of</strong> PPI <strong>of</strong> acoustic startle is reversed by depletion <strong>of</strong> mesolimbic dopamine.<br />
Psychopharmacology 100:413-416<br />
Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990b) Schizophrenia-like sensorimotor gating<br />
abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology<br />
101:414-420<br />
Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991) Effects <strong>of</strong> spiperone, raclopride, SCH 23390 <strong>and</strong><br />
clozapine on apomorphine <strong>inhibition</strong> <strong>of</strong> sensorimotor gating <strong>of</strong> the startle response in the rat. J<br />
Pharmacol Exp Ther 256:530-256<br />
Swerdlow NR, Caine SB, Geyer MA (1992a) Regionally selective effects <strong>of</strong> intracerebral dopamine<br />
infusion on sensorimotor gating <strong>of</strong> the startle reflex in rats. Psychopharmacology 108:189-195<br />
Swerdlow NR, Caine SB, Braff DL, Geyer MA (1992b) Neural substrates <strong>of</strong> sensorimotor gating <strong>of</strong> the<br />
startle reflex: a review <strong>of</strong> recent findings <strong>and</strong> their implications. J Psychopharmacol 6: 176–190<br />
Swerdlow et al (1992) {local NAC GLU}<br />
Swerdlow NR, Benbow CH, Zisook S, Geyer MA, Braff DL (1993). A preliminary assessment <strong>of</strong><br />
sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33:298-301<br />
Swerdlow NR, Zisook D, Taaid N (1994) Seroquel (ICI 204,636) restores PPI <strong>of</strong> acoustic startle in<br />
apomorphine-treated rats: Similarities to clozapine. Psychopharmacology 114:675-678<br />
Swerdlow NR, lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA (1995a). Increased sensitivity<br />
to the gating-disruptive effects <strong>of</strong> apomorphine after lesions <strong>of</strong> the medial prefrontal cortex or<br />
ventral hippocampus in adult rats. Psychopharmacology 122:27-34<br />
Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR (1995b) Impaired <strong>prepulse</strong><br />
<strong>inhibition</strong> <strong>of</strong> acoustic <strong>and</strong> tactile startle response in patients with Huntington’s disease. J Neurol<br />
Neurosurg Psychiatry 58:192-200<br />
Swerdlow NR (1996) Cortico-striatal substrates <strong>of</strong> cognitive, motor, <strong>and</strong> sensory gating: speculations<br />
<strong>and</strong> implication for psychological function <strong>and</strong> dysfunction. Adv Biol Psychiatry 2:179-207<br />
Swerdlow NR, Varty GB, Geyer MA (1998a) Discrepant findings <strong>of</strong> clozapine effects on PPI <strong>of</strong> startle: is<br />
it the route or the rat? Neuropsychopharmacology 18:50-56<br />
Swerdlow NR, Geyer MA (1998b) Using an animal model <strong>of</strong> deficient sensorimotor gating to study the<br />
pathophysiology <strong>and</strong> new treatments <strong>of</strong> schizophrenia. Schizophrenia Bull 24:285-301<br />
Swerdlow NR, Braff DL, Geyer MA (2000) Animal models <strong>of</strong> deficient sensory gating: what we know,<br />
what we think we know, <strong>and</strong> what we hope to know soon. Behav Pharmacol 11:185-204<br />
Taber MT, Fibiger HC (1995) Electrical stimulation <strong>of</strong> the prefrontal cortex increases dopamine release<br />
in the nucleus accumbens <strong>of</strong> the rat: modulation by metabotropic glutamate receptors. J Neurosci<br />
15:3896-904<br />
Tamminga CA (1998) Schizophrenia <strong>and</strong> glutamatergic transmission. Crit Rev Neurobiol 12:21-36<br />
Van den Bos R, Cools AR (1989) The involvement <strong>of</strong> the nucleus accumbens in the ability <strong>of</strong> rats to<br />
switch cue-directed behaviors. Life Sci 44:367-379<br />
Van den Bos R, Charria-Ortiz GA, Bergmans AC, Cools AR (1991) Evidence that dopamine in the<br />
nucleus accumbens is involved in the ability <strong>of</strong> rats to switch to cue-directed behaviors. Behav Brain<br />
Res 42:107-114.<br />
Van Luijtelaar ELJM, Coenen AML (1986). Two types <strong>of</strong> electrocortical paroxysms in an inbred strain <strong>of</strong><br />
rats. Neuroscience Lett 70:393-397<br />
51
Van Luijtelaar ELJM, Coenen AML (1989). The WAG/Rij model for generalized absence epilepsy. Adv<br />
Epileptology 17:16-21<br />
Van Luijtelaar ELJM, Coenen AML (1997). The WAG/Rij rat model <strong>of</strong> absence epilepsy: ten years <strong>of</strong><br />
research (A compilation <strong>of</strong> papers). Nijmegen University Press, Nijmegen, The Netherl<strong>and</strong>s<br />
Van Luijtelaar EL, Miller CA, Coenen AM, Drinkenburg WH, Ellenbroek BA (1998) Differential effects <strong>of</strong><br />
non-REM <strong>and</strong> REM sleep on sensory gating in rats. Acta Neurobiologiae experimentalis 58:263-270<br />
Van Luijtelaar G, Fabene PF, De Bruin N, Jongema C, Ellenbroek BA, Veening JG (submitted) Is the<br />
lateral septum involved in sensory gating in rats? A Fos study<br />
Varty GB, Higgins GA (1995) Examination <strong>of</strong> drug-induced <strong>and</strong> isolation-induced disruptions <strong>of</strong> PPI as<br />
models to screen antipsychotic drugs. Psychopharmacology 122:15-26<br />
Varty GB, Ralph RJ, Geyer MA (1997) Apomorphine <strong>and</strong> phencyclidine disrupt <strong>prepulse</strong> <strong>inhibition</strong> <strong>and</strong><br />
fear-potentiated startle using a combined paradigm. Soc Neurosci Abstr 23:1363<br />
Varty GB, Higgins GA (1998) dopamine agonist-induced hypothermia <strong>and</strong> disruption <strong>of</strong> PPI: evidence<br />
for a role <strong>of</strong> D3 receptors? Behav Pharmacol 9:445-455<br />
Varty GB, Braff DL, Geyer MA (1999a) Is there a critical developmental 'window' for isolation rearinginduced<br />
changes in PPI <strong>of</strong> the acoustic startle response? Behav Brain Res 100:177-183<br />
Varty GB, Marsden CA, Higgins GA (1999b) Reduced synaptophysin immunoreactivity in the dentate<br />
gyrus <strong>of</strong> PPI-impaired isolation-reared rats. Brain Res 824:197-203<br />
Vaughan HG, Arezzo JC (1988) The neural basis <strong>of</strong> event-related <strong>potentials</strong>. In: TW Picton (Eds)<br />
Human Event-Related Potentials EEG H<strong>and</strong>book (revised series, vol. 3). New York: Elsevier, pp 45-<br />
96<br />
Veening JG, Cornelissen FM, Lieven PAJM (1980) The topical organization <strong>of</strong> the afferents to the<br />
caudate-putamen <strong>of</strong> the rat: a horseradish peroxidase study. Neuroscience 5:1253-1268<br />
Voorn P, Groenewegen H, Gerfen DR (1989) Compartmental organization <strong>of</strong> the ventral striatum <strong>of</strong><br />
the rat: immunohistochemical distribution <strong>of</strong> enkephalin, substance P, dopamine, <strong>and</strong> calciumbinding<br />
protein. J Comp Neurol 289:189–201<br />
Wadenberg MG, Sills TL, Fletcher PJ, Kapur S (2000) Antipsychotic-like effects <strong>of</strong> amoxapine, without<br />
catalepsy, using the PPI <strong>of</strong> the acoustic startle reflex test in rats. Biol Psychiatry 47:670-676<br />
Waldo MC, Freedman R (1986) <strong>Gating</strong> <strong>of</strong> <strong>auditory</strong> <strong>evoked</strong> responses in normal college students.<br />
Psychiatry Res 19:233-239<br />
Waldo MC, Adler LE, Freedman R (1988) Defects in <strong>auditory</strong> sensory gating <strong>and</strong> their apparent<br />
compensation in relatives <strong>of</strong> schizophrenics. Schizophr Res 1:19-24<br />
Waldo MC, Carey G, Myles-Worsley M, Cawthra E, Adler LE, Nagamoto HT, et al (1991) Codistribution<br />
<strong>of</strong> a sensory gating deficit <strong>and</strong> schizophrenia in multi-affected families. Psychiatry Res 39:257-68<br />
Waldo M, Myles Worsley M, Madison A, Byerley W, Freedman R (1995) Sensory gating deficits in<br />
parents <strong>of</strong> schizophrenics. Am J Med Genet 60:506-511<br />
Waldo MC, Cawthra E, Adler LE, Dubester S, Staunton M, Nagamoto H, Baker N, Madison A, Simon J,<br />
Scherzinger A, et al (1994) Auditory sensory gating, hippocampal volume, <strong>and</strong> catecholamine<br />
metabolism in schizophrenics <strong>and</strong> their siblings. Schizophr Res 12:93-106<br />
Wan FJ, Swerdlow (1993) Intra-accumbens infusion <strong>of</strong> quinpirole impairs sensorimotor gating <strong>of</strong><br />
acoustic startle in rats Psychopharmacology 113:103-109<br />
Wan FJ, Geyer MA, Swerdlow NR (1994) Accumbens D2 modulation <strong>of</strong> sensorimotor gating in rats:<br />
Assessing anatomical localization. Pharmacol Biochem Behav 49:155-163<br />
Wan FJ, Geyer MA, Swerdlow NR (1995) Presynaptic dopamine-glutamate interactions in the nucleus<br />
accumbens regulate sensorimotor gating. Psychopharmacology 120:433-441<br />
Wan FJ, Swerdlow NR (1996a) Sensorimotor gating in rats is regulated by different dopamineglutamate<br />
interaction in the nucleus accumbens core <strong>and</strong> shell subregions. Brain Res 722:168-176<br />
Wan FJ, Taaid N, Swerdlow NR (1996b) Do D1/D2 interactions regulate PPI in rats?<br />
Neuropsychopharmacology 14:265-274<br />
Wan FJ, Swerdlow NR (1997) The basolateral amygdala regulates sensorimotor gating <strong>of</strong> acoustic<br />
startle in the rat. Neuroscience 76:715-724<br />
Watson CG, Kucala T, Tilleskjor C, Jacobs L. Schizophrenic birth seasonality in relation to incidence <strong>of</strong><br />
infectious diseases <strong>and</strong> temperature extremes. Arch Gen Psychiatry 41:85-90<br />
Weike AI, Bauer U, Hamm AO (2000) Effective neuroleptic medication removes <strong>prepulse</strong> <strong>inhibition</strong><br />
deficits in schizophrenic patients. Biol Psychiatry 47:61-70<br />
Weinberger NM, Diamond DM (1988) Dynamic Modulation <strong>of</strong> the Auditory System by Associative<br />
Learning. In: Auditory Function: neurological bases <strong>of</strong> hearing, GM Edelman, WE Gall, WM Cowan<br />
(Eds). The Neuroscience Institute (John Wiley & Sons), New York, pp 485-512<br />
Wiley JL (1994) Clozapine’s effects on phencyclidine-induced disruption <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the<br />
acoustic startle response. Pharmacol Biochem Behav 49:1025–1028<br />
Wilkinson LS, Killcross SS, Humby T, Hall FS, Geyer MA, Robbins TW (1994) Social isolation in the rat<br />
produces developmentally specific deficits in PPI <strong>of</strong> the acoustic startle response without disrupting<br />
latent <strong>inhibition</strong>. Neuropsychopharmacology 10:61-72<br />
Williams DJ, Crossman AR, Slater P (1977) The efferent projections <strong>of</strong> the nucleus accumbens in the<br />
rat. Brain Res 130:217-227<br />
Williams MN, Faull RLM (1985) The striatonigral projection <strong>and</strong> nigrotectal neurons in the rat: A<br />
correlated light <strong>and</strong> electron microscopic study demonstrating a monosynaptic striatal input to<br />
identified nigrotectal neurons using a combined degeneration <strong>and</strong> horseradish peroxidase<br />
procedure. Neuroscience 14:991-1010<br />
Wilson CJ (1987) Morphology <strong>and</strong> synaptic connections <strong>of</strong> crossed corticostriatal neurons in the rat. J<br />
Comp Neurol 263:567–580<br />
52
Winer JA (1985) The medial geniculate body <strong>of</strong> the cat. Adv Anat Embryol Cell Biol 86:1-97<br />
Winer JA (1992) The Functional Architecture <strong>of</strong> the Medial Geniculate Body <strong>and</strong> the Primary Auditory<br />
Cortex. In: The Mammalian Auditory Pathway: neuroanatomy, DB <strong>Webs</strong>ter, AN Popper, RR Fay<br />
(Eds). Springer-Verlag, New York, pp 222-409<br />
Wise RA, Bozarth MA (1987) A psychomotor stimulant theory <strong>of</strong> addiction. Psychol Rev 94:469-492<br />
Wise RA, Rompré PP (1989) Brain dopamine <strong>and</strong> reward. Ann Rev Psychol 40:191-225<br />
Witter MP (1989) Connectivity <strong>of</strong> the rat hippocampus. In: V Chan-Palay, C Köhler (Eds), Neurology<br />
<strong>and</strong> Neurobiology, Vol. 52. The hippocampus: New Vistas. Alan R Liss, New York, pp 53-69<br />
Woods CC, Wolpaw JR (1982) Scalp distribution <strong>of</strong> human <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong>. II Evidence for<br />
overlapping sources <strong>and</strong> involvement <strong>of</strong> <strong>auditory</strong> cortex. Electroenceph Clin Neurophysiol 54:25-38<br />
Woods DL, Knight RT, Neville HJ (1984) Bitemporal lesions dissociate <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong> <strong>and</strong><br />
perception. Electroenceph Clin Neurophysiol 57:208-220<br />
Woods DL, Clayworth CC, Knight RT, Simpson GV, Naeser MA (1987) Generators <strong>of</strong> middle <strong>and</strong> long<br />
latency <strong>auditory</strong> <strong>evoked</strong> <strong>potentials</strong>: Implications from studies <strong>of</strong> patients with bitemporal lesions.<br />
Electroenceph Clin Neurophysiol 68:132-148<br />
Woolf NJ, Harrison JB, Buchwald JS (1990). Cholinergic neurons <strong>of</strong> the feline pontomesencephalon: II.<br />
Ascending anatomical projections. Brain Res 520:55-72.<br />
Wu MF, Krueger J, Ison JR, Gerrard RL (1984) Startle reflex <strong>inhibition</strong> in the rat: its persistence after<br />
extended repetition <strong>of</strong> the inhibitory stimulus. J Exp Psychology: Animal Behav Processes 10:221-<br />
228<br />
Wu MF, Jenden DJ, Fairchild MD, Siegel JM (1993) Cholinergic mechanisms in startle <strong>and</strong> PPI: effects<br />
<strong>of</strong> the false cholinergic precursor N-aminodeanol. Behav Neurosci 107:306-316<br />
Yee BK (2000) Cytotoxic lesions <strong>of</strong> the medial prefrontal cortex abolishes the partial reinforcement<br />
extinction effect, attenuates <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the acoustic startle reflex <strong>and</strong> induces transient<br />
hyperlocomotion, while sparing spontaneous object recognition memory in the rat. Neuroscience<br />
95:675-689<br />
Young KA, R<strong>and</strong>opaminell PK, Wilcox RE (1991) Dose <strong>and</strong> time response analysis <strong>of</strong> apomorphine's<br />
effect on PPI <strong>of</strong> acoustic startle. Behav Brain Res 42:43-48<br />
Young KA, R<strong>and</strong>opaminell PK, Wilcox RE (1995) Startle <strong>and</strong> sensorimotor correlates <strong>of</strong> ventral<br />
thalamic dopamine <strong>and</strong> GABA in rodents. Neuroreport 6:2495-2499<br />
Zahm DS, Brog JS (1992) On the significance <strong>of</strong> subterritories in the accumbens part <strong>of</strong> the ventral<br />
striatum. Neuroscience 50:751-767<br />
Zahm DS (1999) Functional-anatomical implications <strong>of</strong> the nucleus accumbens core <strong>and</strong> shell<br />
subterritories. Adv Ventral Striatum Extended Amygdala 877:133-128<br />
Zhang J, Engel JA, Ericson M, Svensson L (1999) Involvement <strong>of</strong> the medial geniculate body in<br />
<strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> acoustic startle. Psychopharmacology 141:189-196<br />
Zhang J, Forkstam C, Engel JA, Svensson L (2000) Role <strong>of</strong> dopamine in <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> acoustic<br />
startle. Psychopharamcology 149:181-188<br />
Zavitsanou K, Cranney J, Richardson R (1999) dopamine antagonists in the orbital prefrontal cortex<br />
reduce PPI <strong>of</strong> the acoustic startle reflex in the rat. Pharmacol Biochem Behav 63:55-61<br />
Zouridakis G, Boutros N (1992) Stimulus parameter effects on the P50 <strong>evoked</strong> response (Brief<br />
Report). Biol Psychiatry 32:839-884<br />
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The goal <strong>of</strong> the present thesis was to analyze (1) to what<br />
extent the various dopaminergic subsystems in the brain<br />
are involved in information processing assessed in the PPI<br />
<strong>and</strong> AEP gating paradigms <strong>and</strong> (2) to what extent these<br />
paradigms represent similar or different aspects <strong>of</strong><br />
information processing.<br />
120
8.1 RAT GENOTYPES WITH DIFFERENCES IN DA PROPERTIES<br />
One <strong>of</strong> the important goals <strong>of</strong> the present thesis was to analyze to what<br />
extent the various DA subsystems in the brain are involved in information<br />
processing assessed in the PPI <strong>and</strong> AEP gating paradigms. Several arguments<br />
have been presented in the introduction (Chapter 1) that indicate that the<br />
nigrostriatal DA system <strong>and</strong> mesolimbic DA system interact <strong>and</strong> therefore we<br />
have posed the question in what way this balance between both systems is<br />
involved in different functions <strong>of</strong> DA in the brain. A non-invasive way <strong>of</strong><br />
investigating effects <strong>of</strong> such a balance is to compare rat genotypes that show<br />
opposite DA properties. Therefore, we have decided to study the possible<br />
differences in four rat genotypes (APO-SUS, APO-UNSUS, WAG/Rij <strong>and</strong> ACI)<br />
before <strong>and</strong> after administration <strong>of</strong> the DA antagonist haloperidol on SWD<br />
(Chapter 3) <strong>and</strong> gating mechanisms (Chapter 5), which have been proposed<br />
to be dependent on DA. These genotypes have been introduced in Chapter 1.<br />
In the study in Chapter 4, we have determined the differences in DA<br />
properties between the four genotypes.<br />
Results from Chapters 3-5 <strong>and</strong> earlier studies are summarized in Table<br />
8.1. These data are further discussed in this section.<br />
Table 8.1 Rat genotypes: DA properties, SWD incidence <strong>and</strong> information<br />
processing<br />
Rat genotypes APO- APO- WAG/Rij ACI<br />
SUS UNSUS<br />
� Apomorphine-induced gnawing + ⎯ ⎯ /(+) ⎯<br />
(1,2,CH 4) � DA ractivity<br />
nigrostriatal system<br />
⎯ + (⎯ )/+ +<br />
� Novelty/amphetamine-induced<br />
locomotor stimulation (1,3,CH 4) �<br />
+ ⎯ + ⎯<br />
DA reactivity mesolimbic system + ⎯ + ⎯<br />
� TH mRNA (SNc), D2/3 binding sites<br />
(CPu), D1 receptor mRNA (CPu) (4)<br />
+ ⎯ ? ?<br />
� SWDs (baseline <strong>and</strong> haloperidol)<br />
(5,6,CH 3)<br />
+ + ⎯ + ⎯<br />
� Prepulse <strong>inhibition</strong> (PPI) (7,CH 5) ⎯ + + +<br />
� Startle reactivity (7,CH 5) + ⎯ ⎯ +<br />
� AEP (N50) gating (CH 5) + + ⎯ +<br />
+ relatively high; ⎯ relatively low; CH= Chapter (REFERENCES 1=Cools et al 1990, 2=Ellenbroek et<br />
al 2000, 3=Cools et al 1997, 4=Rots et al 1996, 5=Inoue et al 1990, 6=Cools <strong>and</strong> Peeters 1992,<br />
7=Ellenbroek et al 1995)<br />
8.1.1 DOPAMINE AND SPIKE-WAVE DISCHARGES (SWDS)<br />
SWDs are thought to be due to synchronized responses <strong>of</strong> thalamo-cortical<br />
(TC) neurons. This synchronization process is considered to be caused by<br />
GABA-mediated output from the reticular thalamic nucleus (RTN) to TC relay<br />
cells (Steriade <strong>and</strong> Llinas 1988).<br />
Buzsáki et al (1990b) have proposed that the SWD incidence is related<br />
to differences in DA properties between rat strains. For instance, the Fisher<br />
344 have more SWDs, a higher tyrosine hydroxylase (TH) activity <strong>and</strong> D2<br />
binding values in the substantia nigra (SN) <strong>and</strong> dorsal striatum indicating<br />
enhanced DA responsiveness for the nigrostriatal system as compared to<br />
Buffalo rats (Buzsáki et al 1990b). This implies that a low nigrostriatal DA<br />
121
activity is related to the occurrence <strong>of</strong> SWDs in these Fisher rats. Direct<br />
evidence confirming this suggestion comes from studies in which an increase<br />
in SWD incidence was found following injections <strong>of</strong> DA blockers<br />
(chlorpromazine <strong>and</strong> acepromazine) into the dorsal striatum (Buzsáki et al<br />
1990a) <strong>and</strong> lesioning <strong>of</strong> the SNc neurons with 6-OHDA) (Danober et al 1998).<br />
Indirect evidence that underlines the role <strong>of</strong> striatal DA in SWD occurrence<br />
comes from studies in which DA agents were systemically injected: DA<br />
agonists decreased <strong>and</strong> DA antagonists increased SWD incidence (Avakyan<br />
<strong>and</strong> Arushanyan 1976; Warter et al 1988; Buzsáki et al 1990a; Inoue et al<br />
1994; Midzianovskaia 1998, 1999).<br />
Cools <strong>and</strong> Peeters (1992) have assessed the occurrence <strong>of</strong> SWDs in the<br />
APO-SUS <strong>and</strong> the APO-UNSUS selection lines <strong>and</strong> they have found that these<br />
rats not only differ in their DA properties, but also in SWD incidence. APO-<br />
SUS rats (six months old) have a higher SWD incidence <strong>and</strong> have been<br />
characterized by a low DA activity <strong>of</strong> the nigrostriatal system versus a high<br />
DA reactivity <strong>of</strong> the mesolimbic system as compared to the APO-UNSUS rats<br />
(Cools et al 1990; Cools <strong>and</strong> Peeters 1992; Rots et al 1996). Another rat<br />
genotype, the WAG/Rij, is considered as an animal model for generalized<br />
absence epilepsy (Coenen et al 1991; Van Luijtelaar <strong>and</strong> Coenen 1986). ACI<br />
rats <strong>of</strong>ten serve as a control rat strain for the WAG/Rij rats, since these rats<br />
appear to be virtually free <strong>of</strong> SWDs (Inoue et al 1990). There is also an<br />
indication that DA might play a modulatory role in the SWD incidence in<br />
WAG/Rij rats, since the DA antagonist fluanisone has been shown to induce a<br />
large increase in spike-wave activity in WAG/Rij's (Inoue et al 1994).<br />
Given above mentioned considerations by Buzsáki et al (1990b) <strong>and</strong><br />
Cools <strong>and</strong> Peeters et al (1992) <strong>and</strong> the findings by Inoue et al (1994), it has<br />
been suggested that certain DA properties in particular rat genotypes occur in<br />
parallel with spike-wave phenomena in the EEG.<br />
Chapter 3 presents the results <strong>of</strong> the study in which it was<br />
investigated whether the four rat genotypes (APO-SUS, APO-<br />
UNSUS, ACI <strong>and</strong> WAG/Rij) form a continuum with respect to the<br />
incidence <strong>of</strong> SWDs at baseline <strong>and</strong> following injection with the<br />
DA antagonist haloperidol. The DA properties <strong>of</strong> these rat<br />
genotypes have already been described in chapter 4. This<br />
presents the opportunity to analyze to what extent centain DA<br />
properties are pathognomic for epileptic rats.<br />
In agreement with previous reports (Inoue et al 1990; Cools <strong>and</strong> Peeters<br />
1992), WAG/Rij's showed significantly more SWDs than ACI rats <strong>and</strong> APO-<br />
SUS rats showed more SWDs compared to APO-UNSUS rats. Earlier data were<br />
extended by the finding that the APO-SUS responded to a systemic injection<br />
<strong>of</strong> haloperidol with an increase in SWD number <strong>and</strong> duration, in contrast to<br />
the APO-UNSUS rats. It was suggested that haloperidol increases the SWD<br />
incidence in APO-SUS rats by enlarging the relative dominance <strong>of</strong> the DA<br />
reactivity in the mesolimbic system. In line with the expectations, the SWD<br />
incidence was also enhanced following haloperidol in WAG/Rij’s compared to<br />
the ACI rats. Finally, since the SWD incidence was higher in APO-SUS than in<br />
WAG/Rij's during baseline <strong>and</strong> following haloperidol, it was hypothesized that<br />
the relative dominance <strong>of</strong> the DA mesolimbic system is smaller in WAG/Rij<br />
than in APO-SUS. However, further research was required to provide evidence<br />
in favor <strong>of</strong> this hypothesis.<br />
122
Given the difference in SWD incidence in WAG/Rij’s <strong>and</strong> ACI rats <strong>and</strong><br />
the involvement <strong>of</strong> DA in SWDs, it was suggested that the WAG/Rij <strong>and</strong> ACI<br />
strains might also differ in DA properties. In order to test whether the four rat<br />
genotypes indeed differ in DA properties, the activity <strong>of</strong> the DA system in<br />
various brain structures was established through assessment <strong>of</strong> behavioral<br />
responses (Chapter 4). First, the DA activity in the dorsal striatum (caudateputamen,<br />
CPu) was measured in a stereotypy paradigm. Secondly, novelty<br />
induced spontaneous activity <strong>and</strong> amphetamine induced locomotor<br />
stimulation was measured on an open-field to determine the DA reactivity in<br />
the ventral striatum (nucleus accumbens, NAC). Non-epileptic ACI <strong>and</strong> APO-<br />
UNSUS rats showed no response to apomorphine, indicating a high DA<br />
activity <strong>of</strong> the nigrostriatal system (Cools et al 1990, Ellenbroek et al 2000,<br />
Chapter 4). These rats also had a low locomotor responsiveness to<br />
novelty/amphetamine, indicating a low DA reactivity <strong>of</strong> the mesolimbic<br />
system (Cools et al 1990, 1997, Chapter 4). Epileptic WAG/Rij’s showed only<br />
a small increase in gnawing following apomorphine <strong>and</strong> an increase in<br />
locomotion in response to novelty/amphetamine on an open-field. Therefore,<br />
WAG/Rij's are characterized by a high DA activity <strong>of</strong> the nigrostriatal system<br />
versus a high DA reactivity <strong>of</strong> the mesolimbic system. Apomorphine-induced<br />
gnawing was far more extensive in the epileptic APO-SUS <strong>and</strong> these rats have<br />
also been shown to have high novelty/amphetamine-induced locomotion<br />
(Cools et al 1990, 1997; Ellenbroek et al 2000, Chapter 4). It was concluded<br />
that the DA activity <strong>of</strong> the nigrostriatal system in the WAG/Rij’s is higher than<br />
in the APO-SUS but lower than in the ACI <strong>and</strong> APO-UNSUS rats. Finally, APO-<br />
SUS <strong>and</strong> WAG/Rij rats have been suggested to posses a high DA reactivity <strong>of</strong><br />
the mesolimbic system as compared to the APO-UNSUS <strong>and</strong> ACI rats.<br />
Given these findings, a model can be proposed that describes the<br />
pathways via which DA could play a modulatory role in SWD incidence <strong>and</strong><br />
that could explain how the DA properties <strong>of</strong> the APO-SUS <strong>and</strong> WAG/Rij might<br />
contribute to the high SWD incidence (see Figures 8.1-8.3).<br />
The mechanism by which nigrostriatal DA has been proposed to<br />
prevent the occurrence <strong>of</strong> SWDs is described by Buzsáki et al (1990a).<br />
Normally, a sustained level <strong>of</strong> firing <strong>of</strong> DA neurons in the SNc provides a<br />
steady inhibitory dorsal striatal (caudate-putamen, CPu) output, thereby<br />
inhibiting the GABAergic projections from the substantia nigra pars reticulata<br />
(SNr) <strong>and</strong> internal globus pallidus (GPi) to the thalamus. Evidence for such an<br />
effect via the SNr has been provided by Depaulis et al (1988). They have<br />
found a decrease in SWDs following suppression <strong>of</strong> SNr neurons by local<br />
infusion <strong>of</strong> GABA-mimetic drugs. This leads to a dis<strong>inhibition</strong> <strong>of</strong> TC neurons.<br />
Dis<strong>inhibition</strong> <strong>of</strong> TC neurons reduces the possibility <strong>of</strong> these neurons to show<br />
synchronized responses thereby decreasing SWD incidence. According to the<br />
apomorphine-induced gnawing data as presented in Chapter 4, it was<br />
proposed that APO-SUS rats have a low DA activity in the nigrostriatal<br />
pathway <strong>and</strong> therefore less dis<strong>inhibition</strong> <strong>of</strong> TC neurons, in contrast to the<br />
other genotypes. This could enhance the possibility <strong>of</strong> the TC neurons to show<br />
synchronized responses <strong>and</strong> consequently increase SWDs in APO-SUS rats<br />
(see pathway in Figure 8.1). Recently, it has been shown that injection <strong>of</strong> the<br />
GABA antagonist picrotoxin in the SNr enhances SWDs (Deransart et al 2000)<br />
which fits in well in the model in Figure 8.1.<br />
Figure<br />
8.1<br />
SNc CPu SNr,GPi TC<br />
DA↓<br />
GABA ↓<br />
GABA ↑<br />
GLU<br />
GLU<br />
Cortex<br />
SWD ↑<br />
123
Both the epileptic APO-SUS <strong>and</strong> WAG/Rij show a strong locomotor response<br />
to novelty/amphetamine (Cools et al 1990, 1997; Chapter 4), indicating a<br />
high DA reactivity in the mesolimbic system. Ventral striatal (nucleus<br />
accumbens, NAC) DA was suggested to play a different role in SWD incidence<br />
(Chapters 3-4). Two pathways were proposed via which a high DA reactivity<br />
in the mesolimbic pathway could induce a high SWD incidence. First, it is<br />
known that the NAC inhibits the SNc (Williams et al 1977; Somogyi et al<br />
1981). Thus, DA activity in the NAC can inhibit the release <strong>of</strong> DA in the CPu<br />
(Kohikawa et al 1996) <strong>and</strong> consequently enhance SWDs (see pathway in<br />
Figure 8.2).<br />
Figure<br />
8.2<br />
GABA ↑<br />
SNc CPu SNr,GPi TC GLU<br />
NAC core<br />
DA↓<br />
DA↑<br />
GABA ↓<br />
VTA<br />
DA↑<br />
GABA ↑<br />
NAC shell<br />
GLU<br />
Cortex<br />
SWD ↑<br />
Secondly, Groenewegen et al (1999) have found evidence for a pathway from<br />
the NAC shell to the ventral pallidum (VP) that projects to the RTN.<br />
Synchronized responses <strong>of</strong> TC neurons that facilitate SWDs are considered to<br />
be caused by GABA-mediated output from the RTN (Steriade <strong>and</strong> Llinas<br />
1988). Therefore, it can be hypothesized that DA activation in the NAC could<br />
result in dis<strong>inhibition</strong> <strong>of</strong> the RTN via the VP thereby enhancing GABAergic<br />
output from the RTN <strong>and</strong> increasing SWD incidence (see pathway in Figure<br />
8.3). The VP has been implicated in the modulation <strong>of</strong> SWD incidence that is<br />
in agreement with above-mentioned considerations. Injection <strong>of</strong> a GABA<br />
antagonist in the VP has been shown to suppress SWDs (Deransart et al<br />
1999).<br />
Figure<br />
8.3.<br />
VTA<br />
DA↑<br />
NAC<br />
shell VP<br />
GABA ↑<br />
GABA ↑<br />
RTN<br />
GABA ↓<br />
TC<br />
GLU<br />
GLU<br />
GLU<br />
GLU<br />
Cortex<br />
SWD ↑<br />
Deransart et al (2000) have found that injections <strong>of</strong> mixed DA D1/D2 or<br />
selective D1 or D2 agonists in the NAC core region decreased SWDs, whereas<br />
antagonists increased SWDs. These findings suggest that low instead <strong>of</strong> high<br />
ventral striatal DA activity is related to the occurrence <strong>of</strong> SWDs. However,<br />
effects <strong>of</strong> microinjections <strong>of</strong> DA agents in the NAC shell on SWD incidence<br />
have not yet been investigated. Therefore, the findings by Deransart et al<br />
(2000) do not exclude the possibility that the high DA reactivity in the ventral<br />
striatum in the APO-SUS <strong>and</strong> WAG/Rij rats (Cools et al 1990, 1997; Chapter<br />
4) could be related to the high SWD incidence in these rats, since the<br />
mesolimbic DA modulation <strong>of</strong> SWDs in these rats could predominantly occur<br />
via the NAC shell-VP-RTN projection as described in Figure 8.3. Further<br />
studies remain to be done in order to test whether injecting a DA agonist into<br />
124
the NAC shell or GABA agonists into the ventral pallidum enhance SWD<br />
incidence.<br />
Rots et al (1996) have performed in situ hybridization for the APO-SUS<br />
<strong>and</strong> APO-UNSUS rats. They have found that APO-SUS rats that show<br />
enhanced behavioral responsiveness to apomorphine have increased TH<br />
transcription in SNc DA cells, elevated D1 receptor gene expression <strong>and</strong><br />
increased D2/D3 -receptor binding in the terminal area <strong>of</strong> the nigrostriatal<br />
projection as compared to the APO-UNSUS. Since no such data are available<br />
for the WAG/Rij's <strong>and</strong> ACI, we have decided to also perform in situ<br />
hybridization for these rats. Biochemical analysis <strong>of</strong> the DA properties <strong>of</strong> the<br />
rat genotypes is currently in progress in order to gain more insight into the<br />
underlying mechanism involved in SWD incidence. Optical densities <strong>of</strong> DA D2<br />
receptor mRNA, TH mRNA <strong>and</strong> DA transporter (DAT) mRNA for the<br />
nigrostriatal <strong>and</strong> mesolimbic DA systems will be determined for the four rat<br />
genotypes. Data from this study have not been presented in this thesis.<br />
Main results <strong>and</strong> conclusions<br />
Dopamine <strong>and</strong> spike-wave discharges Chapter 3<br />
� In agreement with previous reports (Inoue et al 1990; Cools<br />
<strong>and</strong> Peeters 1992), WAG/Rij's showed significantly more<br />
SWDs than ACI rats <strong>and</strong> APO-SUS rats showed more SWDs<br />
compared to APO-UNSUS rats.<br />
� Earlier data were extended by the finding that the APO-SUS<br />
responded to a systemic injection <strong>of</strong> haloperidol with an<br />
increase in SWD number <strong>and</strong> duration, in contrast to the<br />
APO-UNSUS rats. It was suggested that haloperidol<br />
increases the SWD incidence in APO-SUS rats by enlarging<br />
the relative dominance <strong>of</strong> the DA reactivity in the mesolimbic<br />
system.<br />
� In line with the expectations, the SWD incidence was also<br />
enhanced following haloperidol in WAG/Rij’s compared to the<br />
ACI rats.<br />
� Finally, since the SWD incidence was higher in APO-SUS than<br />
in WAG/Rij's during baseline <strong>and</strong> following haloperidol, it was<br />
hypothesized that the relative dominance <strong>of</strong> the DA<br />
mesolimbic system is smaller in WAG/Rij than in APO-SUS.<br />
125
Main results <strong>and</strong> conclusions<br />
Dopamine <strong>and</strong> genotypes Chapter 4<br />
� Non-epileptic ACI <strong>and</strong> APO-UNSUS rats showed no response<br />
to apomorphine, indicating a high DA activity <strong>of</strong> the<br />
nigrostriatal system (Cools et al 1990, Ellenbroek et al 2000,<br />
Chapter 4). These rats also had a low locomotor<br />
responsiveness to novelty/amphetamine, indicating a low DA<br />
reactivity <strong>of</strong> the mesolimbic system (Cools et al 1990, 1997,<br />
Chapter 4).<br />
� Epileptic WAG/Rij’s showed only a small increase in gnawing<br />
following apomorphine <strong>and</strong> an increase in locomotion in<br />
response to novelty/amphetamine on an open-field.<br />
Therefore, WAG/Rij's are characterized by a high DA activity<br />
<strong>of</strong> the nigrostriatal system versus a high DA reactivity <strong>of</strong> the<br />
mesolimbic system.<br />
� Apomorphine-induced gnawing was far more extensive in the<br />
epileptic APO-SUS than in the remaining rat genotypes <strong>and</strong><br />
these rats have also been shown to have high<br />
novelty/amphetamine-induced locomotion (Cools et al 1990,<br />
1997; Ellenbroek et al 2000, Chapter 4).<br />
� It was concluded that the DA activity <strong>of</strong> the nigrostriatal<br />
system in the WAG/Rij’s is higher than in the APO-SUS but<br />
lower than in the ACI <strong>and</strong> APO-UNSUS rats.<br />
� Finally, APO-SUS <strong>and</strong> WAG/Rij rats have been suggested to<br />
posses a high DA reactivity <strong>of</strong> the mesolimbic system as<br />
compared to the APO-UNSUS <strong>and</strong> ACI rats.<br />
8.1.2 DOPAMINE IN INFORMATION PROCESSING<br />
DA agonists have been found to reduce PPI in both healthy human subjects<br />
(Hutchison <strong>and</strong> Swift 1999; Abduljawad et al 1999) <strong>and</strong> in rats (Mansbach et<br />
al 1988; Peng et al 1990; Swerdlow et al 1990a, 1990b, 1992). This effect<br />
has been linked to a hyperactivity <strong>of</strong> DA at ventral striatal (e.g. nucleus<br />
accumbens, NAC) D2 receptors (Swerdlow et al 1991; Wan <strong>and</strong> Swerdlow<br />
1993; Wan et al 1994; Caine et al 1995; Ralph et al 1999). Furthermore, DA<br />
infusion in the anteromedial dorsal striatum (caudate-putamen, CPu) has<br />
been found to disrupt PPI (Swerdlow et al 1992). DA seems to play a<br />
modulatory role in AEP gating as well. DA agonists such as bromocriptine <strong>and</strong><br />
amphetamine have been found to reduce P50 gating in healthy human<br />
subjects (respectively, Adler et al 1994 <strong>and</strong> Light et al 1999). In rats,<br />
amphetamine (1-1.83 mg/kg, IP) also interferes with the suppression <strong>of</strong><br />
cortical <strong>and</strong> hippocampal midlatency components, primarily by decreasing the<br />
amplitude to S1 (Adler et al 1986, 1988; Bickford-Wimer et al 1990; Stevens<br />
et al 1991; 1995, 1996; Johnson et al 1998; Chapter 7). In the study in<br />
126
Chapter 6 it was shown that activation <strong>of</strong> NAC DA D2 receptors by quinpirole<br />
reduces cortical N40-N50 gating, an effect that was predominantly mediated<br />
by its effects on the amplitude to S1. These effects could be prevented by<br />
systemic pretreatment with the DA D2 antagonist haloperidol. So, these<br />
studies show that DA plays a prominent role in PPI <strong>and</strong> is also involved in AEP<br />
gating. Therefore, it was decided to study whether the four rat genotypes<br />
with different DA properties as was shown in Chapter 4 would have<br />
differences in these two gating paradigms in Chapter 5.<br />
Several questions were asked in chapter 5: are PPI <strong>and</strong> AEP<br />
gating disturbed in (a) rats that are marked by a relatively high<br />
DA reactivity <strong>of</strong> the mesolimbic system, namely APOSUS <strong>and</strong><br />
WAG/Rij rats, or in (b) rats that are marked by a relatively high<br />
DA activity <strong>of</strong> the nigrostriatal system, namely APO-UNSUS <strong>and</strong><br />
ACI rats? Furthermore, to what extent is a particular imbalance<br />
between the DA nigrostriatal <strong>and</strong> mesolimbic system (c)<br />
important in PPI <strong>and</strong> AEP gating deficits?<br />
Ellenbroek et al (1995) have found that APO-SUS rats show diminished<br />
PPI as compared to rats <strong>of</strong> the APO-UNSUS genotype. AEP gating has not yet<br />
been studied in the APO-SUS <strong>and</strong> APO-UNSUS rats. One aim <strong>of</strong> the study in<br />
Chapter 5 was to determine whether APO-SUS rats would also have a deficit<br />
in AEP gating as compared to the APO-UNSUS. Another goal was to establish<br />
if two other rat genotypes, the ACI <strong>and</strong> WAG/Rij rats would differ in PPI <strong>and</strong><br />
AEP-gating. Since the APO-SUS rats have a high DA reactivity in the ventral<br />
striatum (Cools et al 1990) <strong>and</strong> given the findings that DA hyperactivity in the<br />
ventral striatum has been implicated in both gating deficits (Swerdlow et al<br />
1991; Wan <strong>and</strong> Swerdlow 1993; Wan et al 1994; Caine et al 1995; Ralph et<br />
al 1999; Chapter 6), it was suggested that the DA characteristics in the APO-<br />
SUS contribute to gating disturbances found in these rats. Therefore, it was<br />
expected that APO-SUS rats would also show an AEP gating deficit. Because<br />
the DA system <strong>of</strong> the APO-UNSUS <strong>and</strong> ACI rats is opposite to that <strong>of</strong> the APO-<br />
SUS (Cools et al 1990, Chapter 4), the former two rat genotypes were<br />
expected to show no deficits. The contribution <strong>of</strong> the DA activity in the dorsal<br />
striatum to gating disturbances was assessed by studying gating in the<br />
WAG/Rij rats, since these rats were suggested to posses a higher DA activity<br />
in the dorsal striatum as compared to the APO-SUS (see Chapter 4), while<br />
both rat genotypes have a high DA reactivity in the ventral striatum (Cools et<br />
al 1990, Chapter 4). When besides a high DA reactivity in the mesolimbic<br />
system, also a high DA activity in the dorsal striatum would play a role in PPI<br />
<strong>and</strong> AEP gating, then WAG/Rij's were expected to show more deficits than the<br />
APO-SUS rats.<br />
In chapter 5, the results are presented <strong>of</strong> the study in which the<br />
genotype effects on AEP gating <strong>and</strong> PPI were investigated. Significant AEP<br />
gating <strong>of</strong> several components was observed at two cortical electrode<br />
positions. <strong>Gating</strong> <strong>of</strong> the vertex N50 was significantly reduced in the WAG/Rij<br />
rats as compared to in the remaining three rat genotypes (APO-SUS, APO-<br />
UNSUS <strong>and</strong> ACI). The effects on the amplitude to S1 partially mediated these<br />
effects. No differences were found in PPI between the ACI <strong>and</strong> WAG/Rij rats:<br />
both showed normal PPI. However, basal startle reactivity was significantly<br />
higher in ACI as compared to the WAG/Rij rats.<br />
127
This study provides evidence for the relative role <strong>of</strong> dorsal <strong>and</strong> ventral<br />
striatal DA on PPI <strong>and</strong> AEP gating. The PPI deficit in APO-SUS <strong>and</strong> not in the<br />
other genotypes, suggests that a DA dominance <strong>of</strong> the ventral striatum<br />
contributes to this deficit. Additionally, since WAG/Rij's posses a high DA<br />
reactivity in the ventral striatum as well, but show normal PPI, it can be<br />
suggested that these rats have a mechanism that protects them from PPI<br />
deficits, possibly through their high DA activity in the dorsal striatum. Ventral<br />
striatal regulation <strong>of</strong> PPI has been suggested to be mediated via the<br />
GABAergic projection to the ventral pallidum that projects to the<br />
pendunculopontine nucleus <strong>of</strong> the tegmentum (PPTg) (Braff <strong>and</strong> Geyer 1990;<br />
Swerdlow et al 1990c; Kodsi <strong>and</strong> Swerdlow 1994; Kretschmer <strong>and</strong> Koch<br />
1998).<br />
In contrast, the N50 gating deficit in WAG/Rij's <strong>and</strong> not in the other<br />
genotypes, suggests that a high DA activity in the dorsal striatum versus a<br />
high DA reactivity in the ventral striatum is necessary for such a gating deficit<br />
to occur. This suggests that the dorsal striatal brain area is also involved in<br />
the DA modulation <strong>of</strong> AEP gating in rats <strong>and</strong> that a general DA hyperactivity<br />
in striatal areas is important in this gating deficit. However, the effects on<br />
N50 gating in WAG/Rij's were partially mediated by the effects on the<br />
amplitude to S1, similar to what has been found with systemic injections <strong>of</strong><br />
amphetamine <strong>and</strong> intra-NAC quinpirole injections in rats (Adler et al 1986,<br />
1988; Bickford-Wimer et al 1990; Stevens et al 1991; 1995, 1996; Johnson<br />
et al 1998; Chapters 6-7). Also, in schizophrenic patients reductions in both<br />
gating <strong>and</strong> amplitude to S1 have been reported (Adler et al 1982; Freedman<br />
et al 1983, 1987; Boutros et al 1991; Judd et al 1992; Cullum et al 1993; Jin<br />
et al 1997; Zouridakis et al 1997; Patterson et al 2000). Given these findings<br />
that the response to S1 (CAMP) is reduced, whereas the response to S2<br />
(TAMP) is not affected, it can be argued that merely the amplitude <strong>and</strong> not<br />
the inhibitory process between S1 <strong>and</strong> S2 is affected by DA<br />
neurotransmission.<br />
The sequence <strong>of</strong> events as illustrated in Figure 8.4 can explain this<br />
reduction in the amplitude to S1 <strong>and</strong> increase in TC ratio (reflecting a<br />
reduction in gating). Jin <strong>and</strong> colleagues (Jin et al 1997; Patterson et al 2000)<br />
have suggested that the reduction in the initial P50 response to S1 could to<br />
be an important contributor to the decrease in gating in schizophrenic<br />
patients. With single-trial analysis they have found that patients have higher<br />
trial-to-trial latency variability (temporal variability or jitter) in S1 P50<br />
responses than normal subjects, while the S2 showed the same variability as<br />
in controls (Jin et al 1997). The authors have proposed that 'jitter' may<br />
contribute to central inhibitory processes. They have suggested that this<br />
'jitter' phenomenon could be linked to the concept <strong>of</strong> 'occlusion' described by<br />
Adler et al (1982): "When a neuronal population is hyperactive, its constant<br />
background discharge makes it less likely, that the majority <strong>of</strong> the neurons<br />
will respond synchronously to the stimulus being studied". It has been argued<br />
that this could consequently lead to smaller amplitudes <strong>and</strong> increased TC<br />
ratios. The hyperactivity was proposed to be due to a lack <strong>of</strong> functional<br />
inhibitory input.<br />
Furthermore, Adler et al (1982) have suggested that the response to<br />
S1 could not have fully activated inhibitory mechanisms, because the<br />
response to S1 itself was already smaller in patients. DA has been proposed<br />
to increase the responsiveness <strong>of</strong> neurons thereby making them hyperresponsive<br />
to multiple afferents (or enhancing occlusion) (Cullum et al 1993;<br />
Waldo et al 1994). Whether this is a good explanation for the DA modulation<br />
<strong>of</strong> AEP gating in WAG/Rij's, could be further studied by using single-trial<br />
128
analysis in order to investigate temporal variability. When this is indeed the<br />
case, it would be expected that WAG/Rij's would have a higher temporal<br />
variability in S1 responses as compared to the other rat genotypes.<br />
Figure 8.4 Hypothesized sequence <strong>of</strong> events explaining the reduction<br />
in both the amplitude to S1 <strong>and</strong> gating: the role <strong>of</strong> DA<br />
S1<br />
Lack <strong>of</strong> inhibitory input<br />
Hyperactive neuronal population<br />
Less likely that specific neurons will<br />
respond synchronously to S1 (occlusion)<br />
No full activation<br />
inhibitory mechanisms<br />
S2<br />
High trial-to-trial latency variability<br />
(temporal variability or jitter)<br />
Smaller amplitude to S1 (CAMP)<br />
Less reduction amplitude to S2 (TAMP)<br />
Higher TC ratio (reduced gating)<br />
From the results as reported in Chapter 5, it was concluded that both<br />
gating processes are regulated differently by DA in the ventral <strong>and</strong> dorsal<br />
striatum. So, this study provides additional evidence for the test specificity <strong>of</strong><br />
PPI <strong>and</strong> AEP gating. Several experiments were proposed to test the following<br />
hypotheses. The first hypothesis is that the low DA activity in the dorsal<br />
striatum <strong>and</strong> high DA reactivity in the ventral striatum in the APO-SUS<br />
contribute to the PPI deficit in these rats. Then, PPI should be normalized<br />
when APO-SUS rats are injected with a DA agonist in the dorsal striatum<br />
<strong>and</strong>/or a DA antagonist in the ventral striatum. Also, PPI deficits should be<br />
induced when APO-UNSUS <strong>and</strong> ACI rats are injected with a DA antagonist in<br />
the dorsal striatum <strong>and</strong> a DA agonist in the ventral striatum. Finally,<br />
WAG/Rij's should show reduced PPI when they are injected with a DA<br />
antagonist in the dorsal striatum. The second hypothesis is that the high DA<br />
activity in the dorsal striatum <strong>and</strong> high DA reactivity in the ventral striatum in<br />
the WAG/Rij contribute to the N50 gating deficit in these rats. Then, AEP<br />
gating should be normalized when WAG/Rij's are injected with a DA<br />
antagonist in the dorsal striatum <strong>and</strong>/or a DA antagonist in the ventral<br />
striatum. Furthermore, AEP gating deficits should be induced when APO-<br />
UNSUS <strong>and</strong> ACI rats are injected with a DA agonist in the ventral striatum<br />
<strong>and</strong> when APO-SUS rats are injected with a DA agonist in the dorsal striatum.<br />
Main results <strong>and</strong> conclusions<br />
129
Dopamine <strong>and</strong> information processing Chapter 5<br />
� <strong>Gating</strong> <strong>of</strong> the vertex N50 was significantly reduced in the<br />
WAG/Rij rats as compared to in the remaining three rat<br />
genotypes (APO-SUS, APO-UNSUS <strong>and</strong> ACI). The effects on<br />
the amplitude to S1 partially mediated these effects.<br />
� No differences were found in PPI between the ACI <strong>and</strong><br />
WAG/Rij rats: both showed normal PPI. However, basal<br />
startle reactivity was significantly higher in ACI as compared<br />
to the WAG/Rij rats.<br />
� This study provides evidence for the relative role <strong>of</strong> dorsal<br />
<strong>and</strong> ventral striatal DA on PPI <strong>and</strong> AEP gating.<br />
� The PPI deficit in APO-SUS <strong>and</strong> not in the other genotypes,<br />
suggests that a DA dominance <strong>of</strong> the ventral striatum<br />
contributes to this deficit.<br />
� In contrast, the N50 gating deficit in WAG/Rij's <strong>and</strong> not in<br />
the other genotypes, suggests that a high DA activity in the<br />
dorsal striatum versus a high DA reactivity in the ventral<br />
striatum is necessary for such a gating deficit to occur.<br />
� Finally, it was concluded that the APO-SUS is a good model<br />
for schizophrenia concerning PPI <strong>and</strong> latent <strong>inhibition</strong><br />
(Ellenbroek et al 1995), but not with respect to the AEP<br />
gating deficit in schizophrenic patients.<br />
8.2 STIMULATION<br />
OF DOPAMINE D2 RECEPTORS IN THE NUCLEUS<br />
ACCUMBENS AND THE EFFECTS ON INFORMATION PROCESSING<br />
As we have mentioned in Chapters 1, 5 <strong>and</strong> 6, stimulation <strong>of</strong> DA D2 receptors<br />
in the mesolimbic terminal region (e.g. NAC) has been shown to reduce PPI<br />
(Swerdlow et al 1990b, 1992; Wan <strong>and</strong> Swerdlow 1993; Wan et al 1994).<br />
Furthermore, the PPI disruption induced by intra-NAC microinjections <strong>of</strong> the<br />
DA D2 agonist quinpirole (10 µg/0.5 µl) has been shown to be antagonized by<br />
pretreatment with haloperidol (0.05-0.1 mg/kg, SC) (Wan <strong>and</strong> Swerdlow<br />
1993). Finally, Wan et al (1994) have found a tendency for quinpirole to be<br />
more effective in the core <strong>and</strong> central accumbens compared to the shell <strong>and</strong><br />
anteromedial accumbens. Also, injector distance from midline was positively<br />
correlated with the PPI-disruptive effect <strong>of</strong> quinpirole (for the 10 µg /0.5 µl<br />
dose). The VP-PPTg pathway has been suggested to be the relay for the<br />
disruptive effects on PPI exerted by the NAC DA system (Braff <strong>and</strong> Geyer<br />
1990; Swerdlow et al 1990c; Kodsi <strong>and</strong> Swerdlow 1994; Kretschmer <strong>and</strong><br />
Koch 1998).<br />
130
It is not clear whether NAC DA D2 receptors are involved in the<br />
DA modulation <strong>of</strong> AEP gating in rats. Amphetamine effects on<br />
AEP gating were only partially antagonized by the D2 antagonist<br />
sulpiride (Stevens et al 1991) <strong>and</strong> the D2 agonist 7-OH-DPAT<br />
did not reduce AEP gating (Ellenbroek et al 1999). Therefore, we<br />
have decided to study the involvement <strong>of</strong> DA D2 receptors in<br />
AEP gating by injecting the DA agonist quinpirole (10 µg/0.5 µl)<br />
bilaterally into the NAC in chapter 6. Furthermore, the possible<br />
antagonistic effect <strong>of</strong> the DA D2 antagonist haloperidol (0.1<br />
mg/kg, SC) was studied.<br />
Considering that the NAC shell <strong>and</strong> core have been found to differ<br />
anatomically as well as functionally as has been discussed in Chapter 1, it was<br />
decided to separately analyze the effects <strong>of</strong> quinpirole on gating parameters<br />
in both these NAC sites (Zahm <strong>and</strong> Brog 1992; Cools et al 1993, 1995;<br />
Prinssen et al 1994; Koshikawa et al 1996; Groenewegen et al 1999a,b;<br />
Zahm 1999).<br />
The results in the present thesis (Chapter 6) have shown that<br />
hippocampal gating was reduced only in the shell-injected rats, whereas<br />
cortical gating was affected by quinpirole when injected in both NAC sites.<br />
Pretreatment with haloperidol (0.1 mg/kg, SC) fully antagonized the<br />
quinpirole effects on cortical gating, but did not affect the quinpirole-induced<br />
reduction in hippocampal gating. As has already been mentioned in paragraph<br />
8.1.2, gating reduction induced by DA activation seems to be mediated<br />
predominantly by the effects on the amplitude to S1. We have presented a<br />
model by which both reduced gating <strong>and</strong> CAMP could be explained based on<br />
the findings <strong>of</strong> Jin <strong>and</strong> colleagues (see Figure 8.4).<br />
In chapter 6, we have proposed the circuitry through which the<br />
differential effects <strong>of</strong> shell <strong>and</strong> core quinpirole injections on hippocampal<br />
versus cortical gating might be explained. There are no direct projections<br />
from the NAC to the hippocampus or cortex, only indirect circuitry's. Indirect<br />
effects <strong>of</strong> stimulation <strong>of</strong> DA receptors in striatal areas on the amplitude to S1<br />
<strong>and</strong> TC ratio are further discussed here <strong>and</strong> a model is presented in Figures<br />
8.5-8.9.<br />
Quinpirole injections in the NAC shell decreased both gating <strong>and</strong> CAMP<br />
as measured on the cortex <strong>and</strong> the hippocampus (Chapter 6). The NAC shell<br />
has an indirect inhibitory projection to the VTA (Groenewegen et al 1999a,b)<br />
via the ventral pallidum (VP) (for review see Heimer et al 1995). The VTA<br />
provides DA inputs to the hippocampal dendate gyrus (DG) <strong>and</strong> cortical areas<br />
such as the entorhinal cortex (EC) <strong>and</strong> medial prefrontal cortex (mPFC)<br />
(Berger et al 1976; Swanson 1982; Björklund <strong>and</strong> Lindvall 1984; Fuxe et al<br />
1985; Descarries et al 1987). Therefore, quinpirole injections in the NAC shell<br />
could have induced a reduction in feedback <strong>inhibition</strong> via the VP (see pathway<br />
in Figure 8.5). DA could locally increase the responsiveness <strong>of</strong> neurons<br />
thereby making them hyper-responsive to multiple afferents (occlusion) that<br />
could decrease synchrony in their response to the <strong>auditory</strong> input, which could<br />
then lead to a decreased amplitude <strong>of</strong> the <strong>evoked</strong> potential to S1 (Cullum et<br />
al 1993, Waldo et al 1994).<br />
Figure<br />
8.5<br />
VTA<br />
NAC<br />
shell VP VT<br />
DG, EC,<br />
mPFC Hippocampal<br />
<strong>and</strong> cortical<br />
DA↑<br />
GABA<br />
↑ GABA ↓<br />
DA↑<br />
gating/CAMP ↓<br />
131
Furthermore, there might be an alternative explanation for the effects <strong>of</strong><br />
quinpirole in the NAC shell on cortical parameters. The VP that is innervated<br />
by the NAC shell, also sends GABAergic fibers directly to the mPFC (for review<br />
see Groenewegen et al 1993, 1999b; Heimer et al 1995). Additionally, the VP<br />
projects to the cortex via the thalamus. Thus, it can be proposed that DA<br />
activation in the NAC shell might lead to a reduction in GABAergic output to<br />
the mPFC (see pathway in Figure 8.6) <strong>and</strong> dis<strong>inhibition</strong> <strong>of</strong> TC cells (see<br />
pathway in Figure 8.7) via the VP. This could have resulted in cortical neurons<br />
to become hyper-responsive. Consequently this leads to occlusion <strong>and</strong> a<br />
reduction in cortical CAMP.<br />
VTA<br />
Figure<br />
8.6<br />
DA↑<br />
Figure<br />
8.7<br />
VTA<br />
NAC<br />
shell VP mPFC Cortical<br />
gating/CAMP ↓<br />
GABA ↑ GABA ↓<br />
NAC<br />
shell<br />
VP<br />
DA↑ GABA<br />
↑ GABA ↓<br />
TC Cortex<br />
GLU ↑<br />
Cortical<br />
gating/CAMP ↓<br />
Quinpirole injections in the NAC core decreased gating <strong>and</strong> CAMP as<br />
measured on the cortex (Chapter 6). Core matrix neurons have been<br />
suggested to send inhibitory projections to the substantia nigra pars reticulata<br />
(SNr) (Groenewegen et al 1999a). The SNr sends GABAergic fibers to the<br />
thalamus that, in turn, innervates the cortex. DA activity in the NAC core can<br />
therefore be suggested to result in a dis<strong>inhibition</strong> <strong>of</strong> TC neurons via the SNr<br />
(see pathway in Figure 8.8). This could have induced the cortical neurons to<br />
become hyper-responsive <strong>and</strong> this could consequently lead to occlusion <strong>and</strong> a<br />
reduction in cortical CAMP.<br />
Figure<br />
8.8<br />
SNc<br />
DA↑<br />
NAC<br />
core<br />
SNr<br />
TC<br />
GABA ↑ GABA ↓<br />
GLU ↑<br />
Cortex<br />
Cortical<br />
gating/CAMP ↓<br />
In Chapter 5, we have found that WAG/Rij's that have a high DA activity in<br />
the dorsal striatum <strong>and</strong> a high DA reactivity in the ventral striatum, have a<br />
N50 gating deficit which was also partially explained by the reduction in N50<br />
CAMP. APO-SUS with a low DA activity in the dorsal striatum <strong>and</strong> ACI <strong>and</strong><br />
APO-UNSUS with low DA reactivity in the ventral striatum did not show<br />
deficits in N50 gating. The high DA activity in the dorsal striatum may<br />
contribute to the N50 gating reduction in WAG/Rij's <strong>and</strong> the high DA reactivity<br />
in the ventral striatum in the APO-SUS may not be a sufficient condition for<br />
the N50 gating deficit to occur. The dorsal striatum provides inhibitory inputs<br />
to the GABAergic neurons in the SNr (Chevalier et al 1985; Deniau <strong>and</strong><br />
Chevalier 1985) <strong>and</strong> subsequently nigrothalamic fibers are directed to the TC<br />
neurons that send projections to the cortex. So, this means that enhancing<br />
DA activity in the dorsal striatum (CPu) can result in a dis<strong>inhibition</strong> <strong>of</strong> TC<br />
neurons via the SNr (see pathway in Figure 8.9). This could induce cortical<br />
neurons to become hyper-responsive <strong>and</strong> consequently lead to occlusion <strong>and</strong><br />
132
a reduction in cortical CAMP, similar to what has been described above for the<br />
effects <strong>of</strong> DA activation in the NAC core.<br />
Figure<br />
8.9<br />
SNc CPu SNr,GPi TC Cortex Cortical<br />
DA ↑ GABA<br />
↑ GABA ↓ GLU ↑ gating/CAMP ↓<br />
According to above described hypotheses this could imply that general striatal<br />
DA activation in the WAG/Rij's could have induced the N50 gating deficit via a<br />
dis<strong>inhibition</strong> <strong>of</strong> TC neurons.<br />
Main results <strong>and</strong> conclusions<br />
Stimulation DA D2 receptors in the NAC <strong>and</strong> AEP gating<br />
Chapter 6<br />
� Hippocampal gating was reduced only in the shell-injected<br />
rats, whereas cortical gating was affected by quinpirole when<br />
injected in both NAC sites.<br />
� Pretreatment with haloperidol fully antagonized the<br />
quinpirole effects on cortical gating, but did not affect the<br />
quinpirole-induced reduction in hippocampal gating.<br />
� <strong>Gating</strong> reduction induced by DA activation seems to be<br />
mediated predominantly by the effects on the amplitude to<br />
S1.<br />
8.3 REDUCTION IN GLUTAMATE ACTIVITY BY KETAMINE AND THE<br />
EFFECTS ON INFORMATION PROCESSING<br />
Besides dopamine, also glutamate has been proposed to play a role in some<br />
<strong>of</strong> the abnormalities in schizophrenia (Javitt 1987; Lathi et al 1995; G<strong>of</strong>f <strong>and</strong><br />
Wine 1997). The glutamate hypothesis <strong>of</strong> schizophrenia is based on the<br />
observation <strong>of</strong> psychotomimetic effects <strong>of</strong> non-competitive N-methyl-Daspartate<br />
(NMDA) receptor antagonists, such as phencyclidine (PCP),<br />
dizocilpine (MK-801) <strong>and</strong> ketamine. Therefore, effects <strong>of</strong> these drugs have<br />
been studied in animal models for information processing disturbances in<br />
schizophrenic patients.<br />
Systemic effects <strong>of</strong> non-competitive NMDA receptor antagonists have<br />
reliably shown to decrease PPI (Geyer et al 1989; Mansbach 1991; Mansbach<br />
<strong>and</strong> Geyer 1991; H<strong>of</strong>fman et al 1993; Bakshi et al 1994; Johansson et al<br />
1994; Wiley 1994). As described in Chapter 1, local effects in the amygdala<br />
or dorsal hippocampus have been suggested to mediate systemic effects <strong>of</strong><br />
non-competitive NMDA antagonists on PPI (Bakshi <strong>and</strong> Geyer 1998). These<br />
effects are probably not modulated by monoamines, since haloperidol did not<br />
antagonize effects <strong>of</strong> PCP on PPI (Geyer et al 1989; Keith et al 1991). Adler et<br />
al (1986) have shown that PCP interferes with the suppression <strong>of</strong> the cortical<br />
N50 response to S2 in the AEP gating paradigm in rats. The by PCP-induced<br />
reduction in AEP gating could be antagonized by haloperidol (Adler et al<br />
1986). Further studies showed (Miller et al 1992) that selective lesioning <strong>of</strong><br />
133
the noradrenergic input with the neurotoxin DSP-4, as well as less selective<br />
depletion <strong>of</strong> monoamines with reserpine, blocked the loss <strong>of</strong> hippocampal<br />
gating induced by PCP <strong>and</strong> MK-801. The authors have suggested that drugs<br />
such as PCP most likely disrupt gating by increasing monoaminergic activity.<br />
Since PCP is also known as a DA reuptake inihibitor, the effects<br />
<strong>of</strong> PCP could be explained in terms <strong>of</strong> DA effects. Therefore, it is<br />
<strong>of</strong> interest to study the influence <strong>of</strong> a more specific NMDA<br />
antagonistic drug such as ketamine in order to establish the<br />
effects on both PPI <strong>and</strong> AEP gating (Chapter 7)<br />
In this thesis (Chapter 7), we have presented a study in which we have<br />
investigated the effects <strong>of</strong> the non-competitive NMDA receptor antagonist<br />
ketamine on both PPI <strong>and</strong> AEP gating. Ketamine disrupted PPI <strong>of</strong> the startle<br />
response <strong>and</strong> even induced <strong>prepulse</strong> facilitation. Second, the same dose <strong>of</strong><br />
ketamine that reduced PPI did not affect sensory gating in the AEP gating<br />
paradigm. In contrast, d-amphetamine diminished gating <strong>of</strong> two <strong>of</strong> the<br />
components <strong>of</strong> the AEP (the N35 <strong>and</strong> P61). We have argued that the<br />
discrepancy between our results with ketamine <strong>and</strong> the results <strong>of</strong> Adler et al<br />
(1986) with PCP could be due to the difference in drugs that were<br />
administered in both studies. PCP is also known to act as a DA reuptake<br />
inhibitor, thereby enhancing the DA activity (Johnson et al 1984; Gerhardt et<br />
al 1987; Koek et al 1989; Akunne et al 1991), whereas Akunne et al (1991)<br />
have demonstrated that ketamine has more selective NMDA antagonistic<br />
properties than PCP. This suggestion is corroborated by the finding that the<br />
PCP-induced disruption <strong>of</strong> AEP gating was antagonized by haloperidol (Adler<br />
et al 1986).<br />
However, at the time we have used different electrode placements<br />
(FP/S) than Adler et al (1986, vertex). Therefore, it is imperative to also<br />
study effects <strong>of</strong> ketamine <strong>and</strong> other non-competitive NMDA receptor<br />
antagonists on the vertex components in future studies. Although we have<br />
administered d-amphetamine to validate the animal model for disturbances in<br />
AEP gating <strong>and</strong> indeed a disruption in gating <strong>of</strong> the N35 <strong>and</strong> P61 components<br />
was found, this difference in electrode position could be a limitation <strong>of</strong> the<br />
study as presented in Chapter 7.<br />
In this experiment another important effect was found, namely the<br />
significant test sequence effect for the ketamine-induced decrease in PPI.<br />
Effects <strong>of</strong> ketamine on PPI were stronger in naive animals than in non-naive<br />
animals. In naive animals, a large decrease <strong>of</strong> PPI <strong>and</strong> even <strong>prepulse</strong><br />
facilitation was found. In non-naive animals, a small <strong>and</strong> non-significant effect<br />
<strong>of</strong> ketamine was found. It was suggested that the animals could have been<br />
less sensitive to the second administration <strong>of</strong> ketamine in the PPI experiment.<br />
These results suggest that it could be important to use a between-group<br />
design to study drug effects in the PPI <strong>and</strong> AEP gating paradigms, instead <strong>of</strong><br />
testing the effects <strong>of</strong> drugs on both types <strong>of</strong> gating in the same session<br />
<strong>and</strong>/or in the same animals.<br />
134
Main results <strong>and</strong> conclusions<br />
Ketamine effect on PPI <strong>and</strong> AEP gating Chapter 7<br />
� Ketamine disrupted PPI <strong>of</strong> the startle response <strong>and</strong> even<br />
induced <strong>prepulse</strong> facilitation.<br />
� The same dose <strong>of</strong> ketamine that reduced PPI did not affect<br />
AEP gating.<br />
� The differential effects <strong>of</strong> ketamine on PPI <strong>and</strong> AEP gating<br />
provide additional evidence for the test specificity <strong>of</strong> both<br />
paradigms.<br />
8.4 TEST SPECIFICITY OF AEP GATING AND PREPULSE INHIBITION<br />
The second important aim <strong>of</strong> the present thesis was to determine to what<br />
extent the AEP gating <strong>and</strong> PPI paradigms represent similar or different<br />
aspects <strong>of</strong> information processing. Similarities <strong>and</strong> differences between both<br />
paradigms have already been discussed in Chapter 1. It was concluded that<br />
PPI <strong>and</strong> AEP gating have neural substrates that show overlap on certain parts,<br />
but also differ on other parts <strong>of</strong> the neural substrate. These similarities <strong>and</strong><br />
differences are summarized in Tables 8.2 <strong>and</strong> 8.3. In this thesis, we have<br />
presented some additional evidence for these considerations that are also<br />
incorporated in this section.<br />
Stimulation <strong>of</strong> DA D2 receptors has been found to affect both PPI<br />
(Swerdlow et al 1990, 1992; Wan <strong>and</strong> Swerdlow 1993; Wan et al 1994) <strong>and</strong><br />
AEP gating (Chapter 6) in rats (see Table 8.2). Several differences were found<br />
between AEP gating <strong>and</strong> PPI (see Table 8.3). First, PPI is reduced at an ISI <strong>of</strong><br />
500 ms as compared to an ISI <strong>of</strong> 100 ms in rats (Ellenbroek et al 1999). In<br />
contrast, significant gating was found for several AEP gating components at<br />
the 200 to 600 ms ISIs <strong>and</strong> no differences were found in gating between<br />
these ISIs (Chapter 2). Secondly, APO-SUS rats show deficits in PPI <strong>and</strong> not<br />
in N50 gating, whereas WAG/Rij's have N50 gating disturbances without<br />
deficits in PPI (Chapter 5). Both these genotypes differ in their DA system.<br />
This suggests that both information processing paradigms have different<br />
underlying neural substrates. Third, PPI has been found to be disrupted by<br />
systemic injections with ketamine (10 mg/kg). The same dose <strong>of</strong> ketamine<br />
did not decrease AEP gating in rats (Chapter 7).<br />
135
Table 8.2 Similarities AEP gating <strong>and</strong> PPI<br />
Similarities<br />
� Long-lasting inhibitory processes in the <strong>auditory</strong> pathway<br />
� <strong>Gating</strong> deficits in schizophrenic patients (1)<br />
� Dependent on genetic factors: also asymptomatic family members (2)<br />
� Trait deficit or biological marker for schizophrenia spectrum disorders:<br />
also subjects with schizotypical personality disorder (3)<br />
� No improvement with typical antipsychotics (haloperidol), normalized<br />
with the atypical antipsychotic clozapine (4)<br />
� Disturbance by DA agonists <strong>and</strong> non-competitive NMDA antagonists (5)<br />
� Nicotinergic agents temporarily restore PPI <strong>and</strong> AEP gating deficits (6)<br />
� Septo-hippocampal system (7) <strong>and</strong> nucleus accumbens DA D2<br />
receptors (CH 6)<br />
CH=Chapter (REFERENCES 1= Braff et al 1978, 1992; Adler et al 1982; 2= Waldo et al 1988, 1995;<br />
Cadenhead et al 1999, 3= Cadenhead 1993, 1999, 2000; 4= Freedman et al 1983; Adler et al 1990;<br />
Nagamoto 1996, 1999; Kumari et al 1999; Light et al 2000; 5= Mansbach et al 1988; Swerdlow et al<br />
1996; Adler et al 1986; Bickford-Wimer et al 1990; Stevens et al 1995; Geyer et al 1989; Mansbach<br />
et al 1991; Mansbach <strong>and</strong> Geyer 1991; Adler et al 1986; Miller et al 1992; 6= Kumari et al 1996;<br />
Stevens et al 1997; Stevens <strong>and</strong> Wear 1997; 7= Caine et al 1992; Koch 1996; Bickford-Wimer et al<br />
1990; Miller <strong>and</strong> Freedman 1995; Stevens et al 1998).<br />
Table 8.3 Differences between AEP gating <strong>and</strong> PPI<br />
Differences PPI AEP gating<br />
� Output parameter � Reflex � EEG/AEP<br />
� Stimuli � Prepulse-startle � Identical<br />
� Maximal <strong>inhibition</strong> healthy<br />
subjects<br />
� ISI: 100-120 ms,<br />
reduced at 500 ms<br />
(1)<br />
� ISI: 500 ms,<br />
reduced 1000 ms (2)<br />
� ISI: 150, 500 ms<br />
<strong>and</strong> not at 75 ms (4)<br />
� Deficit schizophrenic patients � ISI: 100-120 ms<br />
(3*)<br />
� DA D2/D3 agonist 7-OH-<br />
DPAT<br />
� Reduction (5) � No effect (6)<br />
� PCP-induced reduction <strong>and</strong><br />
haloperidol pretreatment<br />
� Not antagonized (7) � Antagonized (8)<br />
� 5-HT2 receptor agonist DOI � Decrease (9) � Increase (10)<br />
� Apomorphine in neonatal DA � Differentiation (11) � No differentiation<br />
lesioned versus sham<br />
lesioned rats<br />
(12)<br />
No correlation (humans <strong>and</strong><br />
rats) (6, 13)<br />
� �<br />
� Rats: Interstimulus interval � 500
8.5 THE HUMAN P50 AND THE RAT HOMOLOGUE IN AEP GATING?<br />
In the introduction (Chapter 1) <strong>and</strong> Chapter 2, we have mentioned that it is<br />
still not clear what the equivalent is for the human P50 in the rat. Some<br />
propose an early vertex component (the P13) (Miyazato et al 1995, 1996,<br />
1999a,b, 2000; Reese 1995a,b), whereas others suggest that the vertex N40-<br />
N50 is the equivalent (Adler et al 1986, 1998; Boutros et al 1994, 1997a,b).<br />
Several arguments have been presented that are in favor <strong>of</strong> the N40-N50<br />
(that is thought to be modulated by the hippocampus) being the rat<br />
homologue <strong>of</strong> the human P50 (see Table 8.4). In contrast, other arguments<br />
have been presented by Miyazato <strong>and</strong> colleagues that suggest that the rat<br />
P13 (that is thought to be modulated by the pendunculopontine nucleus <strong>of</strong><br />
the tegmentum, PPTg) <strong>and</strong> not the N40-N50 is the equivalent <strong>of</strong> the human<br />
P50 (see Table 8.4). Especially the drug-induced changes by amphetamine,<br />
cocaine <strong>and</strong> nicotine <strong>of</strong> N40-N50 gating are strong argument in favor <strong>of</strong> this<br />
component, since such findings have not been reported for the rat P13.<br />
However, the slow wave sleep (SWS)-induced effects on the P13 <strong>and</strong> not on<br />
the N40-N50 <strong>and</strong> the shorter latency <strong>of</strong> the P13 are important arguments<br />
against the N40-N50 <strong>and</strong> in favor <strong>of</strong> the P13.<br />
Considering these limitations, more research should be focussed on<br />
comparing properties <strong>of</strong> the human P50 <strong>and</strong> <strong>of</strong> rat midlatency AEP<br />
components. It is <strong>of</strong> particular importance to investigate which <strong>of</strong> the above<br />
mentioned rat AEP components respond in a similar fashion to certain<br />
experimental manipulations such as varying the interstimulus interval (ISI)<br />
<strong>and</strong> repetitive stimulation. The lack <strong>of</strong> st<strong>and</strong>ardized methods in the AEP<br />
gating research is one <strong>of</strong> the remaining problems. Depending on which<br />
component the authors are interested in, completely different recording<br />
settings have been used. Future comparative AEP gating research should use<br />
st<strong>and</strong>ardizing methods to allow comparison between data from various<br />
laboratories. Until agreement is reached <strong>and</strong> sufficient experimental evidence<br />
has been provided regarding the rat homologue for the human P50, it is<br />
better to report data on multiple AEP components instead <strong>of</strong> focussing on just<br />
one perhaps arbitrary component.<br />
The amount <strong>of</strong> P50 gating in humans has been found to be<br />
dependent on repetitive stimulation <strong>and</strong> the interstimulus<br />
interval (ISI) (respectively, Starr et al 1997; Boutros <strong>and</strong> Belger<br />
1999 <strong>and</strong> Adler et al 1982; Freedman et al 1983). In Chapter<br />
2, we therefore present the study in which we have determined<br />
the effects <strong>of</strong> repetitive stimulation (Experiment 1) <strong>and</strong> various<br />
ISIs (Experiment 2) on rat AEP components.<br />
The results suggest that gating is not limited to a restricted cortical<br />
area or a single midlatency component. <strong>Gating</strong> was found for the vertex P17,<br />
N22, N50 <strong>and</strong> FP/S P13, N35, P61. <strong>Gating</strong> was not significant for the vertex<br />
N14 <strong>and</strong> P30 components. The same results were obtained with respect to<br />
gating <strong>of</strong> these components in Chapter 5. Furthermore, repetitive stimulation<br />
<strong>and</strong> ISI affected gating <strong>of</strong> several rat AEP components in a similar fashion as<br />
has been shown for the human P50. Components such as the vertex P17 <strong>and</strong><br />
N22 showed a decrease in gating within several S1-S2 presentations, mainly<br />
due to a decrease in amplitude to S1 (Experiment 1). <strong>Gating</strong> for most<br />
components (such as the P17, N22, N50 <strong>and</strong> FP/S N35, P61) was ISI<br />
137
dependent (Experiment 2), but there was no interval in the 200 to 600 ms<br />
range at which optimal gating occurred. The ISI effects on gating <strong>of</strong> the<br />
vertex components were due to an increase <strong>of</strong> the amplitude to S2.<br />
Table 8.4 Arguments in favor <strong>of</strong> the N40-N50 <strong>and</strong> P13 being P50<br />
homologues<br />
N40-N50 P13<br />
� Both the rat N40-N50 <strong>and</strong> the human P50 are<br />
midlatency EPs that demonstrate filtering to<br />
paired <strong>auditory</strong> stimuli separated by 500 msec<br />
(1).<br />
� Like the human P50, the rat N40-N50 shows<br />
recovery <strong>of</strong> the response to S2 when the ISI<br />
between S1 <strong>and</strong> S2 is prolonged (2).<br />
� Rat N40-N50 gating is sensitive to stimulus<br />
change which has also been shown for the<br />
human P50, when utilizing non-identical pairs in<br />
the AEP gating paradigm (3).<br />
� Rat N40-N50 gating has been shown to be<br />
sensitive to pharmacological manipulation with<br />
amphetamine which has recently also been<br />
reported for the human P50 (4).<br />
� Amphetamine-induced disturbances in rat N40-<br />
N50 gating have been shown to be normalized<br />
by nicotine due to a reduction in the amplitude<br />
to S2. Nicotine (either by smoking or chewing<br />
nicotine gum) also produced normalization <strong>of</strong><br />
P50 gating in both schizophrenic patients <strong>and</strong><br />
normal non-gating individuals by reducing the<br />
testing amplitude (5).<br />
� Cocaine abusers have reduced <strong>auditory</strong> P50<br />
amplitude <strong>and</strong> suppression compared to normal<br />
controls. A similar effect <strong>of</strong> cocaine has been<br />
described for the rat N40-N50 (6).<br />
� The human P50 <strong>and</strong><br />
rat P13 have been<br />
shown to be<br />
diminished during slow<br />
wave sleep (SWS) <strong>and</strong><br />
reappear with waking<br />
amplitudes during REM<br />
sleep. In contrast, the<br />
N40-N50 is present<br />
during waking <strong>and</strong><br />
SWS <strong>and</strong> reduced<br />
during REM sleep (7).<br />
� Attenuation <strong>of</strong><br />
response at stimulus<br />
rates exceeding 1 Hz<br />
has been reported for<br />
the human P50 <strong>and</strong><br />
rat P13 (8).<br />
� The P13 has the<br />
same polarity as the<br />
human P50 <strong>and</strong> has a<br />
shorter latency. In<br />
contrast, the rat N40<br />
is a negative<br />
component with a long<br />
latency in a species<br />
with a small brain (9).<br />
CH=Chapter (REFERENCES 1= Adler et al 1982, 1986; 2= Adler et al 1982, 1986; Freedman et al<br />
1983; Zouridakis <strong>and</strong> Boutros 1992; 3= Guterman et al 1992; Boutros et al 1997a; 4= Adler et al<br />
1986, 1988; Stevens et al 1991, 1995, 1996; Johnson et al 1998; Light et al 1999; 5= Adler et al<br />
1990, 1992; Stevens et al 1995; 6= Fein et al 1996; Boutros et al 1994, 1997b; 7= Erwin <strong>and</strong><br />
Buchwald 1986a; Miyazato et al 1995, 1999a; 8= Erwin <strong>and</strong> Buchwald 1986b; Miyazato et al 1995;<br />
9= Miyazato et al 1999a)<br />
The findings that the vertex N14 <strong>and</strong> P30 showed no gating <strong>and</strong> that<br />
the FP/S P13 was not ISI dependent suggests that these components are<br />
unlikely homologues for the human P50. Also, results in Chapter 7 show that<br />
gating <strong>of</strong> the FP/S P13 was not affected by amphetamine which underlines<br />
this suggestion. The findings that gating <strong>of</strong> the vertex P17 <strong>and</strong> N22<br />
components was decreased with repetitive stimulation <strong>and</strong> was ISI<br />
dependent, makes these components the most likely c<strong>and</strong>idates for the rat<br />
homologue <strong>of</strong> the human P50. Also, since both rat components had a shorter<br />
latency than 50 msec <strong>and</strong> because <strong>of</strong> the smaller brains in rats, these<br />
components are more likely c<strong>and</strong>idates. Although the vertex N50 showed<br />
significant gating that was ISI dependent, N50 gating did not decrease with<br />
repetitive stimulation. Furthermore, it can be argued that a smaller latency is<br />
138
more probable <strong>and</strong> therefore a rat N50 as compared to the human P50 might<br />
be an argument against this rat component being the equivalent. However,<br />
like the human P50 (Light et al 1999), this components has been shown to be<br />
dependent on DA manipulation (Adler et al 1986, 1988; Stevens et al 1991,<br />
1995, 1996; Johnson et al 1998; Chapter 6). Finally, although gating <strong>of</strong> the<br />
FP/S N35 was not reduced with repetitive stimulation, it is the most likely<br />
FP/S equivalent because <strong>of</strong> two reasons. First, this component showed<br />
significant gating that was ISI dependent (Chapter 2). Secondly, N35 gating<br />
could be reduced by amphetamine (Chapter 7).<br />
An important consideration is, however that similar ISI <strong>and</strong> repetitive<br />
stimulation effects have also been mentioned for the human N100 component<br />
(Davis et al 1966; Fruhstorfer et al 1970). Although these findings for the<br />
N100 could be dependent on the properties <strong>of</strong> the preceding P50, this could<br />
mean that specific rat AEP components showing above-mentioned<br />
characteristics might actually correspond to either the human P50 or N100. Of<br />
interest is the recent preliminary report by Boutros et al (1999). They have<br />
found that schizophrenic patients have difficulty in 'gating out' irrelevant input<br />
<strong>and</strong> 'gating in' relevant input at the early pre-attentive stage (P50), but also<br />
at the later early-attentive stage (N100). Furthermore, they also discuss the<br />
earlier data found by Waldo et al (1988). Waldo et al (1988) have studied two<br />
defects in schizophrenic patients <strong>and</strong> their relatives. They have found that<br />
both P50 gating <strong>and</strong> a reduction in the amplitude <strong>of</strong> the N100 wave (which<br />
has been related to a failure to attend to particular features <strong>of</strong> interest in a<br />
stimulus) occur together in schizophrenics (even in very good prognosis,<br />
mildly ill subjects). In contrast, the defect in the gating <strong>of</strong> P50 occurs in half<br />
<strong>of</strong> the relatives, whereas N100 amplitudes are not diminished. Both Waldo et<br />
al (1988) <strong>and</strong> Boutros et al (1999) have interpreted these results as follows:<br />
"relatives with the P50 gating defect can compensate for that defect at a<br />
subsequent stage <strong>of</strong> information processing, as demonstrated by their large<br />
amplitude N100 wave, whereas schizophrenic patients cannot".<br />
More comparative studies are necessary to establish which <strong>of</strong> the rat<br />
AEP components can be considered as the rat homologue for the human P50.<br />
Since the human P50 has been found to be sensitive to stimulus change<br />
(Guterman et al 1992), we have done a study using non-identical pairs to<br />
investigate which rat AEP components are similarly affected by this particular<br />
experimental manipulation as the human P50. Data from this study have not<br />
been presented in this thesis. However, we are currently in progress<br />
analyzing the data.<br />
Main results <strong>and</strong> conclusions<br />
Effects <strong>of</strong> repetitive simulation <strong>and</strong> the interstimulus interval on<br />
AEP gating Chapter 2<br />
� <strong>Gating</strong> is not limited to a restricted cortical area or a single<br />
midlatency component.<br />
� The findings that the vertex N14 <strong>and</strong> P30 showed no gating<br />
<strong>and</strong> that the FP/S P13 was not ISI dependent suggests that<br />
these components are unlikely homologues for the human<br />
P50. Also, results in Chapter 7 show that gating <strong>of</strong> the FP/S<br />
P13 was not affected by amphetamine which underlines this<br />
suggestion.<br />
139
� The findings that gating <strong>of</strong> the vertex P17 <strong>and</strong> N22<br />
components was decreased with repetitive stimulation <strong>and</strong><br />
was ISI dependent, makes these components the most likely<br />
c<strong>and</strong>idates for the rat homologue <strong>of</strong> the human P50. Also,<br />
since both rat components had a shorter latency than 50<br />
msec <strong>and</strong> because <strong>of</strong> the smaller brains in rats, these<br />
components are more likely c<strong>and</strong>idates.<br />
� Although the vertex N50 showed significant gating that was<br />
ISI dependent, N50 gating did not decrease with repetitive<br />
stimulation. Furthermore, it can be argued that a smaller<br />
latency is more probable <strong>and</strong> therefore a rat N50 as<br />
compared to the human P50 might be an argument against<br />
this rat component being the equivalent. However, like the<br />
human P50 (Light et al 1999), this components has been<br />
shown to be dependent on DA manipulation (Adler et al<br />
1986, 1988; Stevens et al 1991, 1995, 1996; Johnson et al<br />
1998; Chapter 6).<br />
� Finally, although gating <strong>of</strong> the FP/S N35 was not reduced<br />
with repetitive stimulation, it is the most likely FP/S<br />
equivalent because <strong>of</strong> two reasons. First, this component<br />
showed significant gating that was ISI dependent (Chapter<br />
2). Secondly, N35 gating could be reduced by amphetamine<br />
(Chapter 7).<br />
� An important consideration is, however that similar ISI <strong>and</strong><br />
repetitive stimulation effects have also been mentioned for<br />
the human N100 component (Davis et al 1966; Fruhstorfer<br />
et al 1970).<br />
� Future comparative AEP gating research should use<br />
st<strong>and</strong>ardizing methods to allow comparison between data<br />
from various laboratories.<br />
8.6<br />
IMPLICATIONS FOR FUTURE RESEARCH ON ANIMAL MODELS FOR<br />
DISTURBANCES IN AEP GATING AND PREPULSE INHIBITION<br />
In this thesis, evidence was provided for a differential role <strong>of</strong> the DA<br />
subsystems in PPI <strong>and</strong> AEP gating. A DA dominance <strong>of</strong> the mesolimbic system<br />
was proposed to be <strong>of</strong> importance in PPI, whereas a general striatal DA<br />
hyperactivity was suggested to modulate AEP gating. However, DA<br />
modulation <strong>of</strong> AEP gating was shown to be mediated predominantly through<br />
its effects on the amplitude to S1. Several hypothetical pathways were<br />
presented via which these DA effects could influence AEP gating <strong>and</strong> the<br />
amplitude to S1. Further studies on the striatal circuitry's remain to be done<br />
in order to elucidate the mechanisms underlying these effects. Single-trial<br />
analyses can be a useful approach in these studies. DA -induced reduction in<br />
the amplitude to S1 could be caused by an increase in responsiveness <strong>of</strong><br />
neurons thereby making them hyper-responsive to multiple afferents which<br />
could lead to temporal variability <strong>and</strong> consequently to smaller amplitudes.<br />
Since this has been suggested for both the DA effects in rats <strong>and</strong> also in<br />
140
schizophrenic patients, this could be an interesting approach for comparative<br />
AEP gating research.<br />
We have presented a review <strong>of</strong> the similarities <strong>and</strong> differences between<br />
the AEP<br />
gating <strong>and</strong> PPI paradigms. Furthermore, we have provided some<br />
additional evidence for the test specificity <strong>of</strong> both gating measures. So, it can<br />
be concluded that both paradigms could separately provide valuable<br />
information concerning disturbances in gating mechanisms implicated in<br />
schizophrenia. Especially since the atypical antipsychotic clozapine has<br />
recently been shown to normalize both gating measures in patients, both<br />
paradigms can be considered as interesting models for preclinical research on<br />
new antipsychotic drugs.<br />
8.7 REFERENCES<br />
Abduljawad<br />
KA, Langley RW, Bradshaw CM, Szabadi E (1999) Effects <strong>of</strong> bromocriptine <strong>and</strong> haloperidol<br />
on <strong>prepulse</strong> <strong>inhibition</strong>: comparison <strong>of</strong> the acoustic startle eyeblink response <strong>and</strong> the N1/P2 <strong>auditory</strong><strong>evoked</strong><br />
response in man. J Psychopharmacol 13:3-9<br />
A dler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R (1982) Neurophysiological<br />
evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol<br />
Psychiatry 17:639-654<br />
Adler LE, Rose G, Freedman<br />
R (1986) Neurophysiological studies <strong>of</strong> sensory gating in rats: effects <strong>of</strong><br />
amphetamine, phencyclidine, <strong>and</strong> haloperidol. Biol Psychiatry 21: 787–798<br />
Adler LE, Pang K, Gerhardt G, Rose GM (1988) Modulation <strong>of</strong> the gating <strong>of</strong> <strong>auditory</strong><br />
<strong>evoked</strong> <strong>potentials</strong><br />
by norepinephrine: pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry<br />
24:179-190<br />
Adler LE, Gerhardt<br />
GA, Franks R, Baker N, Nagamoto H, Drebing C, Freedman R (1990) Sensory<br />
physiology <strong>and</strong> catecholamines in schizophrenia <strong>and</strong> mania. Psychiatry Res 31:297-309<br />
Adler LE, H<strong>of</strong>fer LH, Griffith J, Waldo M, Freedman R (1992) Normalization <strong>of</strong> deficient sensory<br />
gating<br />
in the relatives <strong>of</strong> schizophrenics by nicotine. Biol Psychiatry 32:607-616<br />
Adler LE, Hope C, H<strong>of</strong>fner LD, Stephen C, Young D, Herhardt G (1994) Bromocriptine<br />
impairs P50<br />
<strong>auditory</strong> sensory gating in normal control subjects. Biol Psychiatry 35:630<br />
Adler LE, Olincy A, Waldo M, Harris JG, Griffith JG, Stevens K, Flach K, Nagamoto<br />
H, Bickford P,<br />
Leonard S, Freedman R (1998) Schizophrenia, sensory gating <strong>and</strong> nicotine receptors. Schizophr Bull<br />
24:189-202.<br />
Ak unne HC, Reid AA, Thurkauf A, Jacobson AE, de Costa BR, Rice KC, Heynes MP, Rothman RB (1991)<br />
[3 H)1-[2-(2-Thienyl) cyclohexyl piperidine labels two high affinity binding sites in human cortex:<br />
further evidence for phencyclidine binding sites associated with the biogenic amine reuptake<br />
complex. Synapse 8:289–300<br />
Avakyan RM, Arushanyan EB (1976)<br />
Effects <strong>of</strong> catecholaminergic drugs on epileptogenic properties <strong>of</strong><br />
the caudate nucleus. Neurosc Behav Physiol 7:13-16<br />
Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes<br />
phencyclidine-induced deficits in<br />
sensorimotor gating <strong>of</strong> the startle response. J Pharmacol Exp Ther 271: 787–794<br />
Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption <strong>of</strong> <strong>prepulse</strong><br />
<strong>inhibition</strong><br />
produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394-8401<br />
Berger B, Thierry AM, Tassin JP, Moyne MA (1976) Dopaminergic innervation <strong>of</strong> the rat prefrontal<br />
cortex: a fluorescence histochemical study. Brain Res 106:133-145<br />
Björklund A, Lindvall O (1984) Dopamine-containing system in the CNS.<br />
In: Björklund A, Hökfelt O<br />
(Eds) Classical transmitters in the CNS, Part I (H<strong>and</strong>book <strong>of</strong> chemical neuroanatomy). Elsevier,<br />
Amsterdam, pp 55-122<br />
Boutros N, Zouridakis G, Overall<br />
(1991) Replication <strong>and</strong> extension <strong>of</strong> the P50 findings <strong>of</strong> the P50<br />
findings in schizophrenia. Clin Electroencephalogr 22:40-45<br />
Bo utros NN, Uretsky N, Berntson G, Bornstein R (1994) Effects <strong>of</strong> cocaine on sensory <strong>inhibition</strong> in rat:<br />
preliminary data. Biol Psychiatry 36:242-248<br />
Boutros NN, Bonnet KA, Millana R, Liu J (1997a)<br />
A parametric study <strong>of</strong> the N40 <strong>auditory</strong> <strong>evoked</strong><br />
potential. Biol Psychiatry 42:1051-1059<br />
Boutros NN, Uretsky N, Liu J (1997b) Effects<br />
<strong>of</strong> repeated cocaine on sensory <strong>inhibition</strong> in rat:<br />
preliminary data. Biol Psychiatry 41:462-466<br />
Boutros NN, Belger A (1999) Midlatency <strong>evoked</strong><br />
<strong>potentials</strong> attenuation <strong>and</strong> augmentation reflect<br />
different aspects <strong>of</strong> sensory gating. Biol Psychiatry 45:917-922<br />
Boutros NN, Belger A, Campbell D, D'Souza CD, Krystal J (1999). Comparison<br />
<strong>of</strong> four components <strong>of</strong><br />
sensory gating in schizophrenia <strong>and</strong> normal subjects: a preliminary report. Psychiatry Res 88:199-<br />
130<br />
Bickford-Wimer PC, Nagamoto H, Johnson R, Adler LE, Egan M, Rose GM, Freedman R (1990) Auditory<br />
sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:174-192<br />
Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Prestimulus effects on human startle<br />
reflex in normals <strong>and</strong> schizophrenics. Psychophysiology 14:339–343<br />
141
Braff DL, Grillon C, Geyer MA (1992) Sensorimotor gating <strong>and</strong> schizophrenia: human <strong>and</strong> animal<br />
model studies. Arch Gen Psychiatry 47:181–188<br />
Buzsáki G, Smith A, Berger S, Fisher LJ, Gage FH (1990a) Petit mal epilepsy <strong>and</strong> Parkinsonian tremor:<br />
hypothesis <strong>of</strong> a common pacemaker. Neuroscience 36:1-14<br />
Buzsáki G, Laszlovszky I, Lajtha A, Vadása C (1990b) Spike-<strong>and</strong>-wave neocortical patterns in rats:<br />
genetic <strong>and</strong> aminergic control. Neuroscience 38:323-333<br />
Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle <strong>prepulse</strong> <strong>inhibition</strong> <strong>and</strong> habituation in<br />
patients with schizotypal personality disorder. Am J Psychiatry<br />
150:1862-1867.<br />
Cadenhead KS, Swerdlow NR, Shafer K, Diaz M, Braff DL (1999) Modulation <strong>of</strong> the startle response<br />
<strong>and</strong> laterality in schizophrenic patients, their relatives <strong>and</strong> schizotypical personality<br />
disorder:<br />
evidence <strong>of</strong> inhibitory deficits. Proc Am Acad Neuropsychopharmacology 136.<br />
Cadenhead<br />
KS, Light GA, Geyer MA, Braff DL (2000). Sensory gating deficits assessed by the P50<br />
event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry<br />
157:55-59<br />
Caine SB, Geyer MA, Swerdlow NS (1992) Hippocampal modulation <strong>of</strong> acoustic startle response <strong>and</strong><br />
<strong>prepulse</strong> <strong>inhibition</strong> in the rat. Pharmacol Biochem Behav 43:1201–1208<br />
Caine SB, Geyer MA, Swerdlow NR (1995) Effects <strong>of</strong> D3/D2 dopamine receptor agonists <strong>and</strong><br />
antagonists on PPI <strong>of</strong> acoustic startle in the rat. Neuropsychopharmacology<br />
12:139-145<br />
Chevalier G, Vacher S, Deniau JM, Desban M (1985). Dis<strong>inhibition</strong> as a basic process in the expression<br />
<strong>of</strong> striatal function I: The striatonigral influence on tecto-spinal/tecto-diencephalic neurons.<br />
Brain<br />
Res 334: 215–226<br />
Coenen<br />
AM, Drinkenburg WH, Peeters BW, Vossen JM, Van Luijtelaar EL (1991). Absence epilepsy <strong>and</strong><br />
the level <strong>of</strong> vigilance in rats <strong>of</strong> the WAG/Rij strain. Neurosci Biobehav Rev 15: 259-263.<br />
Cools AR, Brachten R, Heeren D, Willemen A, Ellenbroek B (1990) Search after neurobiological pr<strong>of</strong>ile<br />
<strong>of</strong> individual-specific features <strong>of</strong> Wistar rats. Brain Res Bull 24:49-69<br />
Cools AR, Peeters BW (1992) Differences in spike-wave discharges in two rat selection lines<br />
characterized by opposite dopaminergic activities. Neurosci Lett 134:253-256<br />
Cools AR, de Beltran KK, Prinssen EPM, Koshikawa N (1993) Differential role <strong>of</strong> core <strong>and</strong> shell <strong>of</strong> the<br />
nucleus accumbens in jaw movements <strong>of</strong> rats. Neurosc Res Comm 14:55-61<br />
Cools AR, Miwa Y, Koshikawa N (1995) Role <strong>of</strong> dopamine D1 <strong>and</strong> D2 receptors in the nucleus<br />
accumbens in jaw movements <strong>of</strong> rats: a critical role <strong>of</strong> the shell. Eur J Pharmacology<br />
286:41-47<br />
Cools AR, Ellenbroek BA, Gingras MA, Engbersen A, Heeren D (1997). Differences in vulnerability <strong>and</strong><br />
susceptibility to dexamphetamine in Nijmegen high <strong>and</strong> low responders to novelty: a dose-effect<br />
analysis <strong>of</strong> spatio-temporal programming <strong>of</strong> behaviour. Psychopharmacology 132:181–187<br />
Cullum<br />
CM, Harris JG, Waldo MC, Smern<strong>of</strong>f E, Madison A, Nagamoto HT, Griffith J, Adler LE <strong>and</strong><br />
Freedman R (1993) Neurophysiological <strong>and</strong> neuropsychological evidence for attentional dysfunction<br />
in schizophrenia. Schizophr Res 10:131-141<br />
Danober<br />
L, Deransart C, Depaulis A, Vergnes M, Marescaux C (1998) Pathophysiological mechanisms<br />
<strong>of</strong> genetic absence epilepsy in the rat. Prog Neurobiol<br />
55:27-57<br />
Davis H, Mast T, Yoshie N, Zerlin S (1966) The slow response <strong>of</strong> the human cortex to <strong>auditory</strong> stimuli:<br />
recovery process. Electroenceph Clin Neurophysiol 21: 105-113<br />
Deniau JM, Chevalier G (1985) Dis<strong>inhibition</strong> as a basic process in the expression <strong>of</strong> striatal functions<br />
II: The striato-nigral influence on thalamocortical cells <strong>of</strong> the ventromedial<br />
thalamic nucleus. Brain<br />
Res 334:227–233<br />
Depaulis<br />
A, Vergnes M, Marescaux C, Lannes B, Warter JM (1988) Evidence that activation <strong>of</strong> GABA<br />
receptors in the substantia<br />
nigra suppresses spontaneous spike-<strong>and</strong>-wave discharges in the rat.<br />
Brain Res 488:20-29<br />
Deransart<br />
C, Riban V, Lê BT, Marescaux C, Depaulis A (1999) Evidence for the involvement <strong>of</strong> the<br />
pallidum in the modulation<br />
<strong>of</strong> seizures in a genetic model <strong>of</strong> absence epilepsy. Neurosc Lett<br />
265:131-134<br />
Deransart<br />
C, Riban V, Lê BT, Marescaux C, Depaulis A (2000) Dopamine in the striatum modulates<br />
seizures in a generatic<br />
model <strong>of</strong> absence epilepsy in the rat. Neuroscience 100:335-344<br />
Descarries TW, Lemay B, Doucet G, Berger B (1987) Regional <strong>and</strong> laminar density <strong>of</strong> the dopamine<br />
innervation in adult rat cerebral cortex. Neuroscience 21:807-824<br />
Ellenbroek BA, Geyer MA, Cools AR (1995) The behavior <strong>of</strong> APO-SUS rats in animal models with<br />
construct validity for schizophrenia. J Neurosci 15: 7604–7611<br />
Ellenbroek BA, van Luijtelaar G, Frenken M, Cools AR (1999) Sensory gating in rats: lack <strong>of</strong> correlation<br />
between <strong>auditory</strong> <strong>evoked</strong> potential gating <strong>and</strong> PPI. Schizophr Bull<br />
25:777-788<br />
Ellenbroek BA, Sluyter F, Cools AR (2000) The role <strong>of</strong> genetic <strong>and</strong> early environmental factors in<br />
determining apomorphine susceptibility. Psychopharmacology 148:124-131<br />
Erwin RJ, Buchwald JS (1986a) Midlatency <strong>evoked</strong> responses: Differential effects <strong>of</strong> sleep in the<br />
human. Electroenceph Clin Neurophysiol 65:383-392<br />
Erwin RJ, Buchwald JS (1986b) Midlatency <strong>evoked</strong> responses: Differential recovery cycle<br />
characteristics. Electroenceph Clin Neurophysiol 64:417-423<br />
Fein G, Biggens C, Mackay S (1996) Cocaine abusers have reduced <strong>auditory</strong> P50 amplitude <strong>and</strong><br />
suppression compared to both normal controls <strong>and</strong> alcoholics. Biol Psychiatry 39: 955-965<br />
Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD (1983) Neurophysiological evidence for a<br />
defect in inhibitory pathways in schizophrenia: comparison <strong>of</strong> medicated <strong>and</strong> drug-free patients.<br />
Biol<br />
Psychiatry 18:537-551<br />
Freedman<br />
R, Adler LE , Gerhardt GA, Waldo M, Baker N, rose GM, Drebing C, Nagamoto H, Bickford-<br />
Wimer P <strong>and</strong> Franks R (1987) Neurobiological studies <strong>of</strong> sensory gating in schizophrenia. Schizophr<br />
Bull 13:669-678<br />
142
Fruhstorfer H, Soveri P, Järviletho T (1970) Short-term habituation <strong>of</strong> the <strong>auditory</strong> <strong>evoked</strong> response in<br />
man. Electroenceph Clin Neurophysiol 28:153-161<br />
Fuxe K, Agnati LF, Kalia<br />
M, Goldstein M, Andersson K, Härfstr<strong>and</strong> A (1985) Dopaminergic system in<br />
the brain <strong>and</strong> pituitary. In: Fluckiger E, Muller EE, Thorner MO (Eds) The dopaminergic system<br />
(Basic <strong>and</strong> clinical aspects <strong>of</strong> neuroscience). Springer-Verlag,<br />
Berlin, pp 11-25<br />
Gerhardt GA, Pang K, Rose GM (1987) In vivo electrochemical demonstration <strong>of</strong> the presynaptic<br />
actions <strong>of</strong> phencyclidine in rat caudate nucleus. J Pharmacol Exp Ther 241:714–721<br />
Geyer MA, Braff DL, Mansbach RS (1989) Failure <strong>of</strong> haloperidol to block the disruption<br />
<strong>of</strong> sensory<br />
motor gating induced by phencyclidine <strong>and</strong> MK801. Biol Psychiatry 25:169A–170A<br />
G <strong>of</strong>f DC, Wine L (1997) Glutamate in schizophrenia: clinical <strong>and</strong> research implications.<br />
Schizophr Res<br />
27:157–168<br />
Graham FK, Murray GM (1977) Discordant effects <strong>of</strong> weak prestimulation on magnitude<br />
<strong>and</strong> latency <strong>of</strong><br />
the blink reflex. Physiol Psychol 5:108-114<br />
Groenewegen HJ,<br />
Berendse HW, Haber SN (1993) Organization <strong>of</strong> the output <strong>of</strong> the ventral pallidal<br />
system in the rat: ventral pallidal efferents. Neuroscience 57:113-142<br />
Groenewegen HJ, Galis de Graaf Y, Smeets WJ<br />
(1999a) Integration <strong>and</strong> segregation <strong>of</strong> limbic corticostriatal<br />
loops at the thalamic level: an experimental tracing study in rats. J Chem Neuroanatomy<br />
16:167-185<br />
Groenewegen HJ, Wright CI, Beijer AV, Voorn P (1999b) Convergence <strong>and</strong> segregation <strong>of</strong> ventral<br />
striatal inputs <strong>and</strong> outputs. Ann NY Acad Sci 877:49-63<br />
Guterman Y, Josiassen<br />
RC, Bashor TR Jr (1992) Attentional influence on the P50 component <strong>of</strong> the<br />
<strong>auditory</strong> event-related brain potential. Int J Psychophysiol 12:197-209<br />
Heimer L, Zahm DS, Alheid GF (1995) Basal ganglia. In: Paxinos G (Eds) The rat nervous system.<br />
Academic Press, San Diego.<br />
H<strong>of</strong>fman HS, Searle JL (1968) Acoustic <strong>and</strong> temporal factors in the avocation<br />
<strong>of</strong> startle. J Acoust Soc<br />
Am 43:269-282<br />
H<strong>of</strong>fman DC, Donovan H, Cassela<br />
JV (1993) The effects <strong>of</strong> haloperidol <strong>and</strong> clozapine on the disruption<br />
<strong>of</strong> sensorimotor gating induced by the non-competitive glutamate antagonist MK-801.<br />
Psychopharmacology<br />
111:339–344<br />
Hutchison KE, Swift R (1999) Effect <strong>of</strong> d-amphetamine on PPI <strong>of</strong> the startle reflex in humans.<br />
Psychopharmacology 143:394-400<br />
Inoue M, Peeters B, Van Luijtelaar E, Vossen<br />
J, Coenen A (1990) Spontaneous occurrence <strong>of</strong> spikewave<br />
discharges in five inbred strains <strong>of</strong> rats. Physiol Behav 48:199-201<br />
Inoue M, Ates N, Vossen JMH, Coenen<br />
AML (1994) Effects <strong>of</strong> the neuroleptanalgesic Fentanyl-<br />
Fluanisone (Hypnorm) on spike-wave discharges in epileptic rats. Pharmacol Biochem Behav 48:<br />
547-551<br />
Javitt CD (1987) Negative schizophrenic symptomatology <strong>and</strong> the PCP (phencyclidine) model <strong>of</strong><br />
schizophrenia. Hillside J Clin Psychiatry 9:12–35<br />
Jin Y, Potkin<br />
SG, Patterson JV, S<strong>and</strong>man CA, Hetrick WP, Bunney WE Jr (1997) Effects <strong>of</strong> P50<br />
temporal variability on sensory gating in schizophrenia. Psychiatry Res 70:71-81<br />
Johansson C, Jackson DM, Svensson L (1994) The atypical<br />
antipsychotic, remoxipride, blocks<br />
phencyclidine-induced disruption <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> in the rat. Psychopharmacology 116:37–442<br />
Johnson SW, Haroldson PE, H<strong>of</strong>fer BJ, Freedman R (1984) Presynaptic dopaminergic<br />
activity <strong>of</strong><br />
phencyclidine in rat caudate. J Pharmacol Exp Ther 229:321–332<br />
Jo hnson RG, Stevens KE, Rose GM (1998) 5-Hydroxytryptamine2 receptors modulate <strong>auditory</strong> filtering<br />
in the rat. J Pharmacol Exp Ther 285:643-650<br />
Ju dd LL, McAdams L, Budnick N <strong>and</strong> Braff (1992) Sensory gating deficits in schizophrenia: new<br />
results. Am J Psychiatry 149:488-493<br />
Ke ith VA, Mansbach RS, Geyer MA (1991) Failure <strong>of</strong> haloperidol to block the effects <strong>of</strong> phencyclidine<br />
<strong>and</strong> dizocilpine on <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> startle. Biol Psychiatry 30:557–566<br />
Koch M (1996) The septo-hippocampal system<br />
is involved in <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the acoustic startle<br />
response in rats. Behav Neurosci 110:468–493<br />
Kodsi MH, Swerdlow NR (1995) Propels <strong>inhibition</strong> in the rat is regulated by ventral<br />
<strong>and</strong> caudodorsal<br />
striato-pallidal circuitry. Behav Neuroscience 109:912-928<br />
Koek W, Colpaert FC, Woods JH, Kamenka JM (1989)<br />
The phencyclidine (PCP) analog N-[1- (2-benzo<br />
(B) thiophenyl) cyclohexyl] piperidine shares cocaine-like but not other characteristic behavioral<br />
effects with PCP, ketamine <strong>and</strong> MK-801. J Pharmacol Exp Ther<br />
250:1019–1027<br />
Koshikawa N, Yoshida Y, Kitamura M, Saigusa T, Kobayashi M, Cools AR (1996) Stimulation <strong>of</strong><br />
acetylcholine or dopamine receptors in the nucleus accumbens differentially alters dopamine release<br />
in the striatum <strong>of</strong> freely moving rats. Eur J Pharmacol 303:13-19<br />
Kretschmer BD, Koch M (1998) The ventral pallidum mediates disruption <strong>of</strong> PPI <strong>of</strong> the acoustic startle<br />
response induced by DA agonists, but not by NMDA antagonists. Brain Res 798:204-210<br />
Kumari V, Checkley SA, Gray JA (1996) Effect <strong>of</strong> cigarette smoking on<br />
PPI <strong>of</strong> the acoustic startle reflex<br />
in healthy male smokers. Psychopharmacology 128:54-60<br />
Kumari V, Soni W, Sharma T (1999) Normalization <strong>of</strong> information processing deficits in schizophrenia<br />
with clozapine. Am J Psychiatry 156:1046-1051<br />
Lathi AC, K<strong>of</strong>fel B, LaPorte D, Tamminga CA (1995) Subanaesthetic<br />
doses <strong>of</strong> ketamine stimulate<br />
psychosis in schizophrenia. Neuropsychopharmacology 13:9–19<br />
Light GA, Malaspina D, Geyer MA, Luber BM, Coleman<br />
EA, Sackeim HA, Braff DL (1999) Amphetamine<br />
disrupts P50 suppression in normal subjects. Biol Psychiatry 46:990-996<br />
143
Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL (2000) Normal P50 suppression in<br />
schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 157:767-<br />
771.<br />
Mansbach<br />
RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in<br />
the rat.<br />
Psychopharmacology 94:507–514<br />
Mansbach RS (1991) Effects <strong>of</strong> NMDA receptor lig<strong>and</strong>s on sensorimotor gating in the rat. Eur J<br />
Pharmacol 202:61–66<br />
Mansbach RS, Geyer MA (1991) Parametric determinants in prestimulus modification <strong>of</strong> acoustic<br />
startle: interaction with ketamine. Psychopharmacology 105:162–168<br />
Midzianovskaia IS (1998) Haloperidol induces changes in the electrocorticogram <strong>of</strong> rats with genetic<br />
petit mal epilepsy. Zh Vyssh Nerv Deiat Im IP Pavlova 48:1111-1114<br />
Midzianovskaia IS (1999) Two types <strong>of</strong> spike wave discharges in the electrocorticogram <strong>of</strong> WAG/Rij<br />
rats, the genetic model <strong>of</strong> absence epilepsy. Zh Vyssh Nerv Deiat Im IP Pavlova 49:855-859<br />
Miller CL, Bickford PC, Luntz-Leybman V, Adler LE, Gerhardt GA, Freedman R (1992) Phencyclidine<br />
<strong>and</strong> <strong>auditory</strong> sensory gating in the hippocampus <strong>of</strong> the rat. Neuropharmacology 31:1041-1048<br />
Miller CL, Freedman R (1995) The activity <strong>of</strong> hippocampal interneurons <strong>and</strong> pyramidal cells during the<br />
response <strong>of</strong> the HPC to repeated <strong>auditory</strong> stimuli. Neuroscience 69:371–381<br />
Miyazato H, Skinner RD, Reese NB, Boop FA, Gracia-Rill E (1995) A middle latency <strong>auditory</strong> <strong>evoked</strong><br />
potential. Brain Res Bull 37:247-255<br />
Miyazato H, Skinner RD, Reese NB, Mukawa J, Garcia-Rill E (1996) Midlatency <strong>auditory</strong> <strong>evoked</strong><br />
<strong>potentials</strong> <strong>and</strong> the startle response in the rat. Neuroscience 75:289-300<br />
Miyazato H, Skinner RD, Garcia-Rill E (1999a) Sensory gating <strong>of</strong> the P13 midlatency <strong>auditory</strong> <strong>evoked</strong><br />
potential <strong>and</strong> the startle response in the rat. Brain Res 822:60-71<br />
Miyazato H, Skinner RD, Garcia-Rill E (1999b) Neurochemical modulation <strong>of</strong> the P13 midlatency<br />
<strong>auditory</strong> <strong>evoked</strong> potential in the rat. Neuroscience 92:911-920<br />
Miyazato H, Skinner RD, Crews T, Williams K, Garcia-Rill E (2000) Serotonergic modulation <strong>of</strong> the P13<br />
midlatency <strong>auditory</strong> <strong>evoked</strong> potential in the rat. Brain Res Bull 51:387-391<br />
Nagamoto HT, Adler LE, Waldo MC, Freedman R (1989) Sensory gating in schizophrenics <strong>and</strong> normal<br />
controls: effects <strong>of</strong> changing stimulation interval. Biol Psychiatry 25:549-561<br />
Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R (1996) <strong>Gating</strong> <strong>of</strong> <strong>auditory</strong> P50 in<br />
schizophrenics: Unique effects <strong>of</strong> clozapine. Biol Psychiatry 40:181-188<br />
Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, Hea R, Griffith J (1999) Auditory<br />
P50 in schizophrenics on clozapine: improved gating parallels clinical improvement<br />
<strong>and</strong> changes in<br />
plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology 39:10-17<br />
Patterson<br />
JV, Jin Y, Gierczak M, Hetrick WP, Potkin S, Bunney WE, S<strong>and</strong>man C (2000) Effects <strong>of</strong><br />
temporal variability on P50 <strong>and</strong> the gating ratio in schizophrenia. Arch Gen Psychiatry<br />
57:57-64<br />
Peng R, Mansbach RE, Braff DL, Geyer MA (1990) A D2 dopamine receptor agonist disrupts<br />
sensorimotor gating in rats: Implications for dopaminergic abnormalities in schizophrenia.<br />
Neuropsychopharmacology 3:211-218<br />
Prinssen<br />
EPM, Balestra, Bemelmans FFJ, Cools AR (1994) Evidence for a role <strong>of</strong> the shell <strong>of</strong> the<br />
nucleus accumbens in oral behavior <strong>of</strong> freely<br />
moving rats. J Neurosci 14:1555-1562<br />
Ralph RJ, Varty GB, Kelly MA, Wang YM, Caron MG, Rubinstein M, Gr<strong>and</strong>y DK, Low MJ, Geyer MA<br />
(1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the<br />
disruption <strong>of</strong><br />
<strong>prepulse</strong> <strong>inhibition</strong> produced by amphetamine in mice. J Neurosci 19:4627-4633.<br />
Reese<br />
NB, Garcia-Rill E, Skinner RD (1995a) Auditory input to the pendunculopontine nucleus: I.<br />
Evoked <strong>potentials</strong>. Brain Res Bull 37:257-264<br />
Reese NB, Garcia-Rill E, Skinner RD (1995b) Auditory input to the pendunculopontine nucleus: II. Unit<br />
responses. Brain Res Bull 37:265-273<br />
Rots NY, Cools AR, Berod A, Voorn P, Rostene W, de Kloet ER (1996) Rats bred for enhanced<br />
apomorphine susceptibility have elevated<br />
tyrosine hydroxylase mRNA <strong>and</strong> dopamine D2-receptor<br />
binding sites in nigrostriatal <strong>and</strong> tuberoinfundibular dopamine systems. Brain Res 710:189-196<br />
Schwarzkopf<br />
SB, Mitra T, Bruno JP (1992) Sensory gating in rats depleted <strong>of</strong> dopamine as neonates:<br />
potential relevance to findings in schizophrenic patients. Biol Psychiatry 31:759-773.<br />
Schwarzkopf SB, Lamberti JS, Smith DA (1993) Concurrent assessment <strong>of</strong> acoustic startle <strong>and</strong><br />
<strong>auditory</strong> P50 <strong>evoked</strong> potential measures <strong>of</strong> sensory <strong>inhibition</strong>. Biol Psychiatry 33:815–828<br />
Sipes TA, Geyer MA (1994) Multiple serotonin receptor subtypes modulate <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the<br />
startle response in rats. Neuropharmacology 33:441-448<br />
Somogyi P, Bolam JP, Totterdell S, Smith AD (1981) Monosynaptic input from the nucleus accumbensventral<br />
striatum region to retrogradely labeled nigrostriatal<br />
neurons. Brain Res 217:245-263<br />
Starr A, Aguinaldo T, Roe HJ, Michalewski HJ (1997) Sequential changes <strong>of</strong> <strong>auditory</strong> processing during<br />
target detection: Motor responding versus mental counting. Electroenceph Clin Neurophysiol<br />
105:201-212<br />
Stevens<br />
KE, Fuller LL, Rose GM (1991) Dopaminergic <strong>and</strong> noradrenergic modulation on amphetamineinduced<br />
changes<br />
in <strong>auditory</strong> gating. Brain Res 555:91–98<br />
Stevens KE, Meltzer J, Rose GM (1995) Nicotinic cholinergic normalization <strong>of</strong> amphetamine-induced<br />
loss <strong>of</strong> <strong>auditory</strong> gating in freely moving rats. Psychopharmacology<br />
119:163-170<br />
Stevens KE, Luthman J, Lindqvist EVA, Johnson RG, Rose GM (1996) Effects <strong>of</strong> neonatal dopamine<br />
depletion on sensory <strong>inhibition</strong> in the rat. Pharmacol Biochem Behav 53:817–823<br />
Stevens KE, Johnson RG, Rose GM (1997) Rats reared in social isolation show schizophrenia-like<br />
changes in <strong>auditory</strong> gating. Pharmacol Biochem Behav 58:1031-1036<br />
144
Stevens KE, Wear KD (1997) Normalizing effects <strong>of</strong> nicotine <strong>and</strong> a novel nicotinic agonist on<br />
hippocampal <strong>auditory</strong> gating in two animal models. Pharmacol Biochem Behav 57:869-874<br />
Stevens KE, Nagamoto H, Johnson RG, Adams CE, Rose GM (1998) Conic acid lesions in adult rats as<br />
a model <strong>of</strong> schizophrenia: changes in <strong>auditory</strong> information processing. Neuroscience 82:701– 708<br />
Swanson LW (1982) The projections <strong>of</strong> the ventral tegmental area <strong>and</strong> adjacent regions: A combined<br />
fluorescent retrograde tracer <strong>and</strong> immun<strong>of</strong>luorescence study in the rat. Brain Res Bull 9:321-353<br />
Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990a) Amphetamine<br />
disruption <strong>of</strong> PPI <strong>of</strong> acoustic startle is reversed by depletion <strong>of</strong> mesolimbic dopamine.<br />
Psychopharmacology 100:413-416<br />
Swerdlow<br />
NR, Braff DL, Masten VL, Geyer MA (1990b) Schizophrenia-like sensorimotor gating<br />
abnormalities in rats following dopamine<br />
infusion into the nucleus accumbens. Psychopharmacology<br />
101:414-420<br />
Swerdlow<br />
NR, Braff DL, Geyer MA (1990c) GABAergic projection from nucleus accumbens to ventral<br />
pallidum mediates<br />
dopamine-induced sensorimotor gating deficits <strong>of</strong> acoustic startle in rats. Brain<br />
Res 532:146-150<br />
Swerdlow<br />
NR, Keith VA, Braff DL, Geyer MA (1991) Effects <strong>of</strong> spiperone, raclopride, SCH 23390 <strong>and</strong><br />
clozapine on apomorphine<br />
<strong>inhibition</strong> <strong>of</strong> sensorimotor gating <strong>of</strong> the startle response in the rat. J<br />
Pharmacol Exp Ther 256:530-256<br />
Swerdlow<br />
NR, Caine SB, Geyer MA (1992) Regionally selective effects <strong>of</strong> intracerebral dopamine<br />
infusion on sensorimotor gating <strong>of</strong> the<br />
startle reflex in rats. Psychopharmacology 108:189-195<br />
Swerdlow NR (1996) Cortico-striatal substrates <strong>of</strong> cognitive, motor, <strong>and</strong> sensory gating: speculations<br />
<strong>and</strong> implication for psychological function <strong>and</strong> dysfunction. Adv Biol Psychiatry 2:179-207<br />
Van Luijtelaar ELJM, Coenen AML (1986) Two types <strong>of</strong> electrocortical paroxysms in an inbred strain <strong>of</strong><br />
rats. Neuroscience Lett 70:393-397<br />
Varty GB, Higgins GA (1998) dopamine agonist-induced hypothermia <strong>and</strong> disruption <strong>of</strong> PPI: evidence<br />
for a role <strong>of</strong> D3 receptors? Behav Pharmacol<br />
9:445-455<br />
Waldo MC, Adler LE, Freedman R (1988) Defects in <strong>auditory</strong> sensory gating <strong>and</strong> their apparent<br />
compensation in relatives <strong>of</strong> schizophrenics. Schizophrenia<br />
Res 1:19-24<br />
Waldo MC, Cawthry E, Adler LE, Dubester S, Staunton M, Nagamoto H, Baker N, Madison A, Simon J,<br />
Scherzinger A, Drebing C, Gerhardt G, Freedman R (1994) Auditory sensory<br />
gating, hippocampal<br />
volume <strong>and</strong> catecholamine metabolism in schizophrenics <strong>and</strong> their siblings. Schizophrenia Res<br />
12:93-106<br />
Waldo<br />
M, Myles Worsley M, Madison A, Byerley W, Freedman R (1995) Sensory gating deficits in<br />
parents <strong>of</strong> schizophrenics.<br />
Am J Med Genet 60:506-511<br />
Wan FJ, Swerdlow (1993) Intra-accumbens infusion <strong>of</strong> quinpirole impairs sensorimotor gating <strong>of</strong><br />
acoustic startle in rats Psychopharmacology 113:103-109<br />
Wan FJ, Geyer MA, Swerdlow NR (1994) Accumbens D2 modulation <strong>of</strong> sensorimotor gating in rats:<br />
Assessing anatomical localization. Pharmacol Biochem Behav<br />
49:155-163<br />
Warter JM, Vergnes M, Depaulis A, Tranchant C, Rumbach L, Micheletti G, Marescaux C (1988) Effects<br />
<strong>of</strong> drugs affecting dopaminergic neurotransmission in rats with spontaneous<br />
petit mal-like seizures.<br />
Neuropharmacology 27:269-274<br />
Wiley<br />
JL (1994) Clozapine’s effects on phencyclidine-induced disruption <strong>of</strong> <strong>prepulse</strong> <strong>inhibition</strong> <strong>of</strong> the<br />
acoustic startle response. Pharmacol<br />
Biochem Behav 49:1025–1028<br />
Williams DJ, Crossman AR, Slater P (1977) The efferent projections <strong>of</strong> the nucleus accumbens in the<br />
rat. Brain Res 130:217-227<br />
Zahm DS, Brog JS (1992) On the significance <strong>of</strong> subterritories in the accumbens part <strong>of</strong> the ventral<br />
striatum. Neuroscience 50:751-767<br />
Zahm DS (1999) Functional-anatomical implications <strong>of</strong> the nucleus accumbens core <strong>and</strong> shell<br />
subterritories. Adv Ventral Striatum Extended<br />
Amygdala 877:133-128<br />
Zouridakis G, Boutros N (1992) Stimulus parameter effects on the P50 <strong>evoked</strong> response (Brief<br />
Report). Biol Psychiatry 32:839-841<br />
Zouridakis G, Boutros NN, Jansen BH (1997) A fuzzy clustering approach to study the <strong>auditory</strong><br />
P50<br />
component in schizophrenia. Psychiatry<br />
Res 69:169-181<br />
145