Gating of auditory evoked potentials and prepulse inhibition - Webs

GATING OF AUDITORY EVOKED POTENTIALS
AND PREPULSE INHIBITION:
AN ANIMAL MODELING APPROACH
DISTINCT RODENT GENOTYPES
AND THE ROLE OF DOPAMINE
NATASJA DE BRUIN
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GATING OF AUDITORY EVOKED POTENTIALS
AND PREPULSE INHIBITION:
AN ANIMAL MODELING APPROACH
DISTINCT RODENT GENOTYPES AND
THE ROLE OF DOPAMINE

The studies described in this thesis were carried out at
� NICI, Department of Psychoneuropharmacology,
University of Nijmegen, The Netherlands
� NICI, Department of Comparative and Physiological
Psychology, University of Nijmegen, The Netherlands
� Health Sciences Center, Department of Psychiatry,
University of Colorado, Denver, Colorado, USA
Cover: Jim DeLutes, http://www.JDLphotos.com
On the bank of a small pond just east of Boulder, Colorado.
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performance by nature. "
ISBN 90-9014705-5
© N.M.W.J. de Bruin, Nijmegen, The Netherlands
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GATING OF AUDITORY EVOKED POTENTIALS
AND PREPULSE INHIBITION:
AN ANIMAL MODELING APPROACH
DISTINCT RODENT GENOTYPES AND
THE ROLE OF DOPAMINE
Een wetenschappelijke proeve op het gebied van de
MEDISCHE WETENSCHAPPEN
PROEFSCHRIFT
Ter verkrijging van de graad van doctor
aan de Katholieke Universiteit Nijmegen,
volgens besluit van het College van Decanen
in het openbaar te verdedigen op
maandag 28 mei 2001
des namiddags om 13.30 uur precies
door
Natasja Maria Wilhelmina Johanna de Bruin
Geboren 20 juli 1970 te Tilburg
NICI
Nijmeegs Instituut voor Cognitie en Informatie

Promotores: Prof. A.R. Cools
Prof. A.M.L. Coenen
Co-Promotores: Dr. B.A. Ellenbroek
Dr. E.L.J.M. Van Luijtelaar
Manuscriptcommissie: Prof. M.J. Zwarts (Voorzitter)
Prof. M.N. Verbaten (UU)
Dr. R.J. Verkes
Voor mijn ouders, Ans en Jan
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CHAPTER 1 General Introduction
CHAPTER 2 Sensory gating of auditory evoked potentials in
rats: effects of repetitive stimulation and the interstimulus
interval
N.M.W.J. de Bruin, B.A. Ellenbroek, W.J. van Schaijk, A.R. Cools,
A.M.L. Coenen, E.L.J.M. van Luijtelaar
Biological Psychology 55 (2001) 95–213
CHAPTER 3 Dopamine characteristics in different rat
genotypes: the relation to absence epilepsy
N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, S.J. Jansen, A.R. Cools,
B.A. Ellenbroek
Neuroscience Research 38 (2000) 165–173
CHAPTER 4 Dopamine characteristics in rat genotypes with
distinct susceptibility to epileptic activity: apomorphineinduced
stereotyped gnawing and novelty / amphetamineinduced
locomotor stimulation
N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, A.R. Cools, B.A.
Ellenbroek
Behavioural Pharmacology 12 (2001) 517–525
CHAPTER 5 Auditory information processing in rat
genotypes with different dopaminergic properties
N.M.W.J. de Bruin, E.L.J.M. van Luijtelaar, A.R. Cools, B.A.
Ellenbroek
Psychopharmacology 156 (2001) 352–359
CHAPTER 6 Hippocampal and cortical sensory gating in
rats: effects of quinpirole microinjections in nucleus
accumbens core and shell
N.M.W.J. de Bruin, B.A. Ellenbroek, E.L.J.M. van Luijtelaar, A.R.
Cools, K.E. Stevens
Neuroscience 105 (2001) 169–180
CHAPTER 7 Differential effects of ketamine on gating of
auditory evoked potentials and prepulse inhibition in rats
N.M.W.J. de Bruin, B.A. Ellenbroek, A.R. Cools, A.M.L. Coenen,
E.L.J.M. van Luijtelaar
Psychopharmacology 142 (1999) 9–17
CHAPTER 8 General Discussion
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Adequate information processing is essential for normal functioning.
Information processing disturbances occur in many neurological and
psychiatric diseases. These deficits have become apparent in schizophrenic
patients. McGhie and Chapman (1961) proposed that symptoms of
schizophrenia could be understood as a disturbance in the filtering or gating
of sensory stimuli and irrelevant thoughts from intruding into conscious
awareness. Theoretically, impairments in gating may lead to sensory
overload, cognitive fragmentation, loss of ego-boundaries, and appraisal in
schizophrenic-spectrum patients (McGhie and Chapman 1961; Venables
1964; Braff and Geyer 1990).
"It is difficult to maintain integrity of thought when sensory
information is unchecked, and floods our attentional resources.
The inability to appropriately inhibit, or gate, sensory
information is formally recognized within the Diagnostic and
Statistical Manual as a clinical feature associated with
schizophrenia (APA, 1994)." (Swerdlow, 1996)
With 'gating' in this thesis, we refer to the normal inhibition of
response that occurs when an acoustic stimulus is preceded by
another stimulus at a short interval (

1.1. DOPAMINERGIC SYSTEM
1.1.1. STRIATUM AND SUBDIVISIONS
The striatum is comprised of the dorsal caudate-putamen (CPu) and the
ventral nucleus accumbens (NAC) (see Figure 1.1.). Therefore, these areas
have also been termed dorsal and ventral striatum. Additionally, the rat
striatum has been subdivided into patch (striosomes) and matrix
compartments (Bolam et al 1988, Gerfen 1985, Kawaguchi et al 1989; for
review see Gerfen 1992b). Besides in rats, this mosaic patch-matrix
organization has been found in primates (Gerfen et al 1985) and in the cat
(Jimenez-Castellanos and Graybiel 1989) as well. These subdivisions have
been found to be biochemically and developmentally distinct and posses
different laminar and regional cortical inputs (Donoghue and Herkenham
1986, Gerfen 1984, 1989; Gerfen et al 1987b). Throughout the majority of
both the dorsal and ventral striatum this patch-matrix organization is found.
However, within the medial part of the NAC these patterns are not as distinct
(Voorn et al 1989; Jongen-Relo et al 1993). Finally, the NAC has been divided
into two compartments, a medioventral 'shell' and a laterodorsal 'core' (see
Figure 1.1.). These NAC subregions have been found to differ anatomically as
well as functionally (Zahm and Brog 1992; Cools et al 1993, 1995; Prinssen
et al 1994; Koshikawa et al 1996; Groenewegen et al 1999a, 1999b; Zahm
1999). The later divisions have also been identified in primates (Meredith et al
1996).
Figure 1.1. Dopaminergic
system: The Striatum
(NAC=nucleus accumbens
[core and shell]; CPu=caudate
putamen) (Adapted from
Paxinos and Watson 1997,
bregma 1.2 mm)
1.1.2. NIGROSTRIATAL SYSTEM
1.1.2.1. Input caudate-putamen
CPu
NAC
core
shell
Cell bodies of neurons forming the major ascending dopaminergic (DA)
pathways to the CPu are located in the brainstem, in the retrorubral nucleus
(RRN, A8), the substantia nigra pars compacta (SNc, A9) and ventral
tegmental area (VTA, A10) (Björklund and Lindvall 1984; Bouyer et al 1984;
Freund et at 1984, Gerfen et al 1987a, Jimenez-Castellanos and Graybiel
1987). The CPu is predominantly innervated by the SNc forming the
nigrostriatal DA system (Veening et al 1980; Björklund and Lindvall 1984;
Fuxe et al 1985) (see Figure 1.2.). Cortical and thalamic fibers provide
excitatory inputs to the CPu (Bouyer et al 1984, Hattori et al 1978, Somogyi
et al 1981) (see Figure 1.3.C.). The DA input to the CPu appears to modulate
the responsiveness of striatal output neurons to these cortical and thalamic
inputs (for review see Gerfen 1992b).
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PFC
NAC
3
OT
CC
2
CE
CPu
Figure 1.2. Dopaminergic system:
The Nigrostriatal, Mesolimbic and Mesocortical DA pathways
1
ME
ARC
SNc
VTA
RN
1. The SNc neurons project mainly to the caudate-putamen or to the dorsal
striatum forming the nigrostriatal DA system. 2. The mesolimbic DA pathway is
formed by neurons that project from the VTA to the ventral striatum, i.e. the
nucleus accumbens, olfactory tubercle and other limbic regions such as the
amygdala 3. The VTA sends axons to the cortical areas, e.g. to the medial
prefrontal cortex and cingulate cortex, which system is called the mesocortical
DA pathway. (ARC=arcuate nucleus of hypothalamus; CC=cingulate
cortex;CE=central amygdala nucleus; CPu=caudate-putamen; LC=locus
ceruleus; ME=median eminence; NAC=nucleus accumbens; OT=olfactory
tubercle; PFC=prefrontal cortex; RN=raphe nuclei; SNc=substantia nigra pars
compacta; VTA=vental tegmental area) (Adapted from Nehlig 1999)
Specific inputs have been identified for the matrix and patch compartments.
Neurons in the VTA, SNc (dorsal tier) and the RRN have DA projections that
are directed to the matrix, whereas neurons in the SNc (ventral tier) and in
the DA Islands in the SNr have DA projections to the patches (Gerfen et al
1987b) (see Figure 1.3.A-B.). Furthermore, corticostriatal neurons in the
superficial parts of layer 5 of the cortex provide inputs to the striatal matrix
compartment, whereas deep layer 5 neurons provide inputs to the striatal
patches (Ferino et al 1987, Wilson 1987).
1.1.2.2. Output caudate-putamen
Projections from GABAergic neurons in the striatum give rise to two
output systems, the direct and indirect pathway which have opposite
regulatory roles (Albin et al 1989, Gerfen et al 1990; for review see
Gerfen 1992b) (see Figure 1.3.C.). The indirect pathway is the projection
to the GABAergic external globus pallidus (GPe) neurons that provide
inhibitory inputs to the subthalamic nucleus (STh) and to the SN (Smith et
al 1990).
LC
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VTA, RRN, (dorsal) SNc
Cortex superficial layer 5
(ventral) SNc
(DA cell Islands) SNr
Cortex deep layer 5
Brainstem:
VTA, RRN,
SNc, SNr
Cortex,
Thalamus
DA
CPu
+
D2
_
+
DA
CPu
matrix
_
_
SNr (GABA)
DA CPu
patches (ventral)
SNc (DA)
GPe
D1
_
+
_
Direct
pathway SNr
(GPi,SNc)
Figure 1.3. Dopaminergic system:
Inputs and outputs of the dorsal striatum
+
Indirect
pathway
_
STh
SNr (DA cell
Islands)
VL,
IL
VM,
MD
PPTg
_
A
B
Thalamus
SC
C
CPu
Cortex
CPu
A. Input and output CPu matrix neurons B. Input and output CPu patch neurons
C. Indirect and direct pathway output CPu
(CPu=caudate-putamen; EC=entorhinal cortex; GPe=globus pallidus externa;
GPi=globus pallidus interna; IL=intralaminar thalamic nuclei; MD=mediodorsal
thalamus; PPTg=pendunculopontine tegmental nucleus; RRN= retrorubral
nucleus; SC= superior colliculus; SNc=substantia nigra pars compacta;
SNr=substantia nigra pars reticulata; STh= subthalamic nucleus;
VL=ventrolateral thalamic nuclei; VM=ventromedial thalamic nuclei; VTA=vental
tegmental area. Neurotransmitters: DA=dopamine; -=GABA/γ-Amino-butyric
acid; + =glutamate)
Neurons in the STh provide an excitatory input to the SNr (Kita et al 1983;
Kita and Kitai 1987a, 1987b; Nakanishi et at 1988). This indirect pathway is
responsible for the tonic activity of GABAergic neurons in the SNr. D2
expressing striatal neurons preferentially project to the GPe (for review
Gerfen 1992b; Fallon and Loughlin 1995). The direct striatonigral pathway
provides inhibitory inputs to the DA and GABAergic neurons in the SNr, SNc
and the internal globus pallidus (GPi) (Chevalier et at 1985, Deniau and
Chevalier 1985). D1 expressing striatal neurons preferentially project to the
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GABAergic SNr neurons (for review Gerfen 1992b; Fallon and Loughlin 1995).
Subsequently, the GABAergic SNr neurons have inhibitory inputs to the
superior colliculus (SC), the pedunculopontine nucleus (PPTg) and the
thalamus (Gerfen 1992b). Nigrothalamic inputs target intralaminar nuclei (IL)
that provide feedback to the striatum. Furthermore, these nigrothalamic
fibers are directed to the ventral and mediodorsal thalamic nuclei that provide
inputs to the (pre) motor / (pre) frontal cortex. For instance, the SNr sends
afferents to the ventral lateral nucleus of the thalamus (VL) that reaches part
of the cortex that innervates the CPu (Aldes 1988), closing the cortico-striatopallido-thalamic
loop (Alexander and Crutcher 1990; Gerfen 1992a).
Neurons giving rise to striatopallidal and striatonigral projections are
separate and intermingled in both striatal patch and matrix compartments.
Matrix neurons provide inputs to the location of the GABAergic neurons in the
SNr, whereas patch neurons provide inputs to the ventral tier of DA neurons
in the SNc and DA cell Islands in the SNr (Gerfen 1984, 1985, Gerfen et al
1985; review Gerfen 1992b) (see Figure 1.3.B-C.).
1.1.2.3. Function nigrostriatal system
Activation of nigrostriatal DA transmission by locally applied DA (Jackson et al
1975b), amphetamine or apomorphine (Kelly et al 1975) induce mainly
stereotyped behaviors, e.g. sniffing, grooming, oral movements but not
locomotion. Furthermore, lesioning the nigrostriatal pathway abolishes
amphetamine-induced stereotyped behavior, while it enhances amphetamineinduced
locomotor stimulation. Another role of DA in the dorsal striatum is
that it allows subjects to switch ongoing behavior with the help of internal
information (Cools et al 1984; Jaspers et al 1984; Oades 1985; Gelissen and
Cools 1988; Jaspers et al 1990; Arts and Cools 1998). Cats with a DA deficit
in the dorsal striatum displayed problems in switching motor programs
without the availability of visual and tactile information (Jaspers et al 1984).
Finally, it has been suggested that the dorsal striatum contributes to nondrug-induced
conditioned reaction time performance (Amalric and Koob 1987;
for review Amalric and Koob 1993).
The dorsal striatum is innervated by glutamatergic projections from the
cortical areas and therefore it is thought to serve as a modulator of cortical
signals (Mogenson 1987). The circuitry as described above (direct and
indirect pathway) is believed to be central in motor processes (Carlsson and
Carlsson 1990; Fuxe et al.1985; Gerfen 1992a). Balanced opposition of the
direct and indirect striatal output systems appears to be responsible for the
generation of normal movements. In rest, the GABAergic SNr neurons are
tonically active. In contrast, during the execution of movement, activity of
these GABAergic neurons is decreased through the direct pathway. Increased
activity in the indirect pathway results in increased tonic activity of SNr
neurons (Alexander and Crutcher 1990) opposing the effect in the direct
pathway.
1.1.3. MESOLIMBIC SYSTEM
1.1.3.1. Input nucleus accumbens
The mesolimbic DA pathway is formed by neurons that project from the VTA
to the ventral striatum (see Figure 1.2.), i.e. the nucleus accumbens (NAC),
olfactory tubercle (OT) and other limbic regions such as the amygdala,
hippocampal dendate gyrus (DG) and lateral septum (Swanson 1982). The
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NAC is innervated by glutamatergic fibers from the hippocampal ventral
subicular area (HPC SUB), entorhinal cortex (EC), medial prefrontal cortex
(mPFC), basolateral amygdala (BLA), midline/intralaminar thalamic nuclei
(IL/ML) and also receives DA afferents from the VTA and SNc (Berendse et al
1992; Groenewegen et al 1987; Heimer et al 1995; Groenewegen et al 1996,
for review Groenewegen et al 1999a, 1999b) (see Figure 1.4.). There are no
afferent systems that exclusively innervate NAC core and shell (Groenewegen
1999b). However, the VTA predominantly projects to the medial and ventral
parts of the shell, but its fibers also terminate in the medial core and the CPu,
whereas the SNc projects mainly to the NAC core and CPu.
SNc
ML,IL,
BLA,
HPC SUB,
mPFC, EC
VTA
DA
+
DA
NAC core
patches
NAC core
matrix
NAC
shell
_
VTA
SNc
_
_
SNr
_
_
mPFC
SN
DA
Thalamus:
VM,IL,MD
+
Thalamus:
ML,MD,
+
RTN
VP
PPTg
_
DA
CPu
Cortex
Cortex
Figure 1.4. Dopaminergic system: Inputs and outputs of the ventral striatum
(BLA=basolateral amygdala; CPu=caudate-putamen; EC=entorhinal cortex; HPC
SUB= hippocampal subiculum; IL=intralaminar thalamic nuclei; MD=mediodorsal
thalamus; ML= midline thalamic nuclei; mPFC=medial prefrontal cortex;
NAC=nucleus accumbens; PPTg=pendunculopontine tegmental nucleus;
RTN=reticular thalamic nucleus; SN=substantia nigra; SNc=substantia nigra pars
compacta; SNr=substantia nigra pars reticulata; VM=ventromedial thalamic
nuclei; VP=ventral pallidum; VTA=vental tegmental area. Neurotransmitters:
DA=dopamine; - =GABA/γ-Amino-butyric acid; + =glutamate)
1.1.3.2. Output nucleus accumbens
Ventral striatal outputs reach the SNc, SNr, VTA and the ventral pallidum (VP)
(Groenewegen et al 1996, for review Groenewegen et al 1999a, 1999b). The
VP in turn projects to the medial prefrontal cortex (mPFC), thalamus, SN and
the pedunculopontine tegmental nucleus (PPTg, a part of the mesencephalic
locomotor region, Schaefer and Michael 1987; for review see Groenewegen et
al 1993) (see Figure 1.4.).
The NAC core patches project to the SNc and the NAC core matrix
sends fibers to the (dorsomedial) SNr (Groenewegen et al, 1999b). The NAC
has been shown to inhibit the SNc (Williams et al 1977; Somogyi et al 1981).
Thus, DA activity in the NAC core patches can inhibit the release of DA in the
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dorsal striatum (Kohikawa et al 1996). So, an interaction between the dorsal
and ventral striatum takes place via this pathway. The medial NAC shell sends
fibers back to the medial VTA.
Furthermore, Groenewegen et al (1999a) have shown that the shell
and core circuits remain largely segregated at the level of the thalamus. The
shell projects predominantly to the mediodorsal (MD), midline (ML) and
reticular (RTN) thalamic nuclei via the VP, whereas the core projects
predominantly to the medial part of the ventromedial (VM) thalamic nucleus,
intralaminar (IL) and mediodorsal (MD) nuclei via the SNr. However, it has
been proposed that at the level of the prelimbic cortex, via the VM and MD
nuclei of the thalamus, shell and core outputs may reach the same cortical
areas (although in different cortical layers) (Groenewegen et al 1999a).
1.1.3.3. Function mesolimbic system
Selective activation of the accumbal DA transmission enhances locomotor
activity but does not cause stereotyped behavior (Pijnenburg and Van Rossum
1973; Jackson et al 1975a; Kelly et al 1975; Pijnenburg et al 1976). Selective
DA lesions of the mesolimbic system abolish amphetamine-induced locomotor
stimulation, while it enhances amphetamine-induced stereotyped behavior
(Kelly et al 1975). DA in the ventral striatum has also been shown to be
involved in the switching of ongoing behavior with the help of external or cuebound
information (Cools et al 1984; Oades 1985; Van den Bos and Cools
1989; Van den Bos et al 1991). Furthermore, the NAC has been proposed to
play a role in the reinforcing properties of both drugs of abuse and of natural
rewards such as food (for review Amalric and Koob 1993). Rewards increase
DA release in the NAC (Di Chiara and Imperato 1988; Kiyatkin 1995) and
attenuation of DA activity in the NAC decreases the reinforcing properties of
these stimuli (Ettenberg 1989; Wise and Bozarth 1987).
Accumbal DA is believed to have a gating function, i.e. it regulates the
information flow from limbic structures such as amygdala and HPC to the
motor nuclei (Mogenson 1987). DA-induced hyperactivity is thought to be
caused by its effect on GABAergic neurons projecting to the VP. It has been
suggested that the NAC shell mainly regulates limbic functions, whereas the
core regulates more motor functions (Heimer and Alheid 1991; Zahm and
Brog 1992). Furthermore, specific behaviors have been shown to be
dependent on DA activation in NAC shell or core. Local NAC injections of DA
agents only induced jaw movements, oral behavior, pivoting and contralateral
turning when injected in the NAC shell (Cools et al 1993, 1995; Prinssen et al
1994; Koshikawa et al 1996; Kitamura et al 1999; Bernstein and Beninger
2000). DA in the NAC core and shell have been found to have different roles
in motivated behavior (respectively, appetitive food stimuli and unpredicted
consumption) (Bassareo and Di Chiara 1999). Finally, psychostimulants and
morphine (when injected IV) have been shown to preferentially increase
extracellular DA in the shell (Pontieri et al 1995).
1.1.4. MESOCORTICAL SYSTEM
The VTA sends axons to cortical areas, e.g. to the medial prefrontal cortex
(mPFC), entorhinal cortex (EC) and cingulate cortex (CC). This system is
called the mesocortical DA pathway (Berger et al 1976; Björklund and
Lindvall 1984; Fuxe et al 1985; Descarries et al 1987) (see Figure 1.2.).
The prefrontal cortex (PFC) is involved in various cognitive processes
such as regulation of working memory and focused attention and these
functions are modulated by the mesocortical DA pathway (Barkley 1998; Le
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Moal and Simon 1991). However, DA in the PFC plays a role in locomotor
activity and reinforcement as well. For instance, attenuation of DA tone in the
PFC by 6-OHDA lesions increases the stimulatory effects of amphetamine
(Carter and Pycock 1980). These effects have been suggested to result from
disinhibition of the excitatory glutamatergic afferents projecting from the PFC
to the VTA and NAC (Taber and Fibiger 1995).
1.1.5. DOPAMINE RECEPTORS AND DRUG ACTION
There are at least five DA receptors (D1-D5) and these are further divided
into two subfamilies (Sibley and Monsma 1992; Civelli et al 1993; Jarvie and
Caron 1993; Strange 1996). The two subfamilies are termed D1-like (D1, D5)
and D2-like (D2, D3, D4). The D1 receptor is expressed in the dorsal and
ventral striatum, in several limbic regions, hypothalamus and thalamus (Jaber
et al 1996). In the striatum, D1 receptors are expressed mainly in the
GABAergic medium-size spiny neurons projecting to the substantia nigra pars
reticulata (SNr). In contrast the D5 receptor is expressed at a lower level and
its mRNA is detected in the HPC and some thalamic nuclei. D2 receptors are
expressed in the dorsal and ventral striatum in GABAergic neurons. D3
receptors are mainly in the ventral striatum, i.e. NAC and OT. The expression
of D3 and D4 receptors is low in the dorsal striatum. The expression of D4
receptors is high in areas such as the frontal cortex (FC), amygdala and
hypothalamus (Jaber et al 1996).
Drugs act on these receptors in different ways. Drugs known as DA
agonists bind to DA receptors in place of DA and directly stimulate these
receptors. In contrast, DA antagonists are drugs that bind but do not
stimulate DA receptors. These drugs can prevent or reverse the actions of DA
by keeping DA from attaching to receptors. Indirect acting drugs such as the
DA agonist amphetamine produce their effects by changing the amount of DA
release and depend on the activity of neurons, whereas direct acting drugs
such as the DA agonist apomorphine act directly on postsynaptic receptors.
1.1.6. CONCLUSIONS
The nigrostriatal and mesolimbic DA systems differ in input, output and in
function. The dorsal striatum (CPu) is predominantly innervated by the cortex
and DA fibers from the SNc. The CPu has the SNr as output area. In contrast,
the NAC of the ventral striatum is innervated by the cortex, several limbic
structures (such as the HPC, BLA) and by the DA fibers from the VTA. The
NAC projects to the VP and back to the VTA (via the NAC shell) and to the
SNr (via the NAC core matrix). Interactions between both DA systems take
place via the projection from the NAC core patches to the SNc that
subsequently innervates the CPu. Also, the input and output of the
patch/matrix compartments differ. The VTA mainly innervates the area with
the patch neurons. Patch neurons send fibers to the DA neurons in the SN. In
contrast, matrix neurons provide inputs to the GABAergic neurons in the SN.
A final distinction can be made between the NAC core and shell. The NAC core
is predominantly innervated by the SNc and has the SNc and SNr as output,
whereas the NAC shell mainly receives DA afferents from the VTA and
projects to the VP and back to the VTA.
The dorsal striatum has a role in stereotyped behavior, the execution
of learned motor programs and the switching of ongoing behavior with the
help of internal information, whereas the ventral striatum is involved in
locomotor activity, goal-oriented (motivated) behavior, switching of ongoing
14

ehavior with the help of external/cue-bound information and has a role in
reinforcement.
This question remains to be answered
The previous section provides an overview of the nigrostriatal and
mesolimbic DA systems. Several arguments have been presented
that indicate that these systems interact. First, DA activity in the
NAC core patches has been suggested to inhibit the release of DA
in the dorsal striatum. Secondly, lesioning the nigrostriatal pathway
abolishes amphetamine-induced stereotyped behavior, while it
enhances amphetamine-induced locomotor stimulation. Third,
selective DA lesions of the mesolimbic system abolish
amphetamine-induced locomotor stimulation, while it enhances
amphetamine-induced stereotyped behavior. This suggests that the
action of DA in the dorsal striatum is dependent upon the action of
DA in the ventral striatum and vice versa. This poses the question
in what way this balance between both DA systems is involved in
different functions of DA in the brain.
1.2. INFORMATION PROCESSING
1.2.1. AUDITORY PATHWAY
Sound is produced by vibrations that result in the alternating compression
and rarefaction (increased or decreased pressure) of the surrounding air
(Kelley 1991). The frequency (in hertz) of the wave/number of peaks that
pass a given point per time-unit determines the pitch (highness/lowness) of a
sound. The amplitude of the wave is the maximum change in air pressure in
either direction and this is correlated with the loudness (decibel) of a sound.
The ascending auditory pathways can be divided into a primary,
lemniscal pathway (1) and non-lemniscal pathways (2) (Andersen et al 1980;
see for reviews Weinberger and Diamond, 1988; Winer, 1992). Lemniscal
neurons have narrow frequency tuning and provide highly specific frequency
information to the auditory cortex, whereas non-lemniscal neurons generally
have broader tuning and greater response lability (Lennartz and Weinberger
1992). Non-lemniscal pathways carry auditory information colored by arousal
from the reticular formation (RF) to several brain areas (Harrison et al 1990;
Simpson and Knight 1993).
1.2.1.1. Primary lemniscal auditory pathway
Sounds that reach the ear set the tympanic membrane in motion and this
motion is conducted to the fluid of the cochlea by the three ossicles of the
middle ear. In turn, motion of the fluid in the cochlea sets the basilar
membrane into motion. The sensory cells (hair cells) that are innervated by
the fibers of the auditory nerve (AN, eight cranial nerve or C.N.VIII) are
located along the basilar membrane and convert the motion of the basilar
membrane into a neural code. The AN carries the auditory information to the
brainstem (see Figure 1.5.). Here, the AN passes through the cochlear nuclei
(CN), which start the neural processing and feature extraction process.
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16
Figure 1.5. Auditory pathway:
Primary lemniscal pathway
(Adapted from
http://www.anatomy.wisc.edu/bs
/text/p12/s/pathway.htm)

Following the CN, the auditory pathway is directed to the next processing
center via the trapezoid body, namely the superior olivary nuclei (SO). These
SO receive axons from both the ipsilateral and contralateral cochlear nuclei
and are suggested to play a role in directional hearing. The medial part of the
SO is concerned with measuring interaural time differences while the lateral
part processes interaural intensity information. After leaving the olives, the
axons progress upward via the bundle of axons that is called the lateral
lemniscus (LL). The lemniscus ascends first through the pons and from there,
the pathway continues upward to the inferior colliculus or IC (midbrain). The
IC is involved in orientation and sound-sight coordination. Also, the
topographic organization according to the spatial location of the sound is
thought to be located in the IC. The pathway is then extended upward
through the brachium to the medial geniculate body (MGB) (below the
forebrain). The MGB is a set of diencephalic nuclei of the ventral thalamus
that serves as a relay center for auditory inputs to the cortex (see Winer
1985, 1992; Imig and Morel 1988 for reviews). The MGB projects to the
primary auditory cortex in the temporal lobe (area 41 and 42) via the
temporal radiation (Pickles 1981; Jones 1985). The auditory cortex is
organized into six neuronal layers (which mainly contain neuronal cell bodies)
and into columns (which reach through the layers). The layers show patterns
of external connections: layer IV receives the input, layer V projects back
towards the MGB and layer VI to the IC. The columns serve more specialized
functions. Finally, the entorhinal cortex (EC) receives input from the primary
auditory cortex through pathways synapsing in the association cortex or via
direct projections (Witter et al 1989).
1.2.1.2. Non-lemniscal pathways
Non-lemniscal pathways diverge from the primary auditory pathway in the
brainstem. Four brainstem auditory relay nuclei (the dorsal and ventral
cochlear nuclei [DCN, VCN], the nucleus of the LL and the IC) sent fibers into
the RF (Powell and Hatton 1969; Carpenter 1978; Irvine and Jackson 1983)
(see Figure 1.6). RF neurons (including cholinergic neurons of the
pedunculopontine tegmental nucleus, PPTg) project via the reticular fasciculus
to the midline and intralaminar nuclei of the thalamus (e.g. the centromedial
nuclei) that subsequently project diffusely to most areas of the cortex (Jones
1985; Woolf et al 1990; Harrison et al 1990; Berendse and Groenewegen
1991; Newman and Ginsberg 1994; Groenewegen and Berendse 1994). The
centromedial thalamic nucleus has been found to directly project to the EC
(Witter et al 1989). In addition, the noradrenergic locus coeruleus (LC) and
the serotonergic raphe nuclei (RN) of the RF project directly and diffusely to
the cortex (Cooper et al 1991). The EC receives these RF projections, as well
as receiving indirect RF influences via multisynaptic thalamocortical and
corticocortical connections (Harrison et al 1990; Witter et al 1989).
Thalamus: ML/IL
(e.g. CM)
RF e.g. PPTg
DCN VCN
LL IC
Cortex (e.g. EC)
ACH
NE 5-HT
LC RN
Figure 1.6. Auditory pathway:
Non-lemniscal pathway
(CM=centromedial nuclei; DCN=dorsal
cochlear nuclei; EC=entorhinal cortex;
IC=inferior colliculus; IL=intralaminar
nuclei; LC=locus ceruleus; LL=lateral
lemniscus; ML=midline nuclei; RF=reticular
formation; RN=raphe nuclei; VCN=ventral
cochlear nuclei; Neurotransmitters:
ACH=acetylcholine; NE=noradrenaline;
5-HT=5-Hydroxytryptamine [serotonin])
17

1.2.2. PREPULSE INHIBITION OF THE ACOUSTIC STARTLE RESPONSE
1.2.2.1. Acoustic startle response (ASR)
The acoustic startle response (ASR) is a short latency motor response
common in most species (e.g. humans, rats and mice) following an
unexpected and intense acoustic stimulus, probably serving a protective
function. In humans, changes in electrical activity in neck muscles can occur
within 9 ms after the onset of an auditory stimulus and within 14 ms in jaw
muscles (Davis et al 1982). In rats, startle occurs within 5 ms in the neck and
8 ms in the hindlegs. Davis et al (1982) have described the circuitry involved
in the ASR after lesioning and electrically stimulating different structures (see
Figure 1.7.). According to these authors, the primary acoustic startle pathway
consists of three synapses onto cochlear root neurons (1), neurons in the
nucleus reticularis pontis caudalis or PnC (2) and motor neurons (3) in the
facial motor nucleus (pinna reflex) or spinal cord (whole body startle). The
PnC can be considered as the interface between the sensory (from cochlear
nuclei to reticular formation) and motor circuit (in the reticular formation and
spinal cord).
18
cochlear
root
neurons
motor neurons
Caudal pontine
reticular
nucleus (PnC)
Figure 1.7. Prepulse inhibition:
Primary acoustic startle circuitry
(Adapted Davis et al 1982)

1.2.2.2. Prepulse inhibition (PPI) in human subjects
In humans, the ASR is usually measured with the eye-blink reflex using
electromyography or EMG of the orbicularis oculi muscle. The ASR can either
be enhanced or inhibited depending on the particular experimental
manipulation (see for reviews Koch and Schnitzler 1997; Koch 1999).
Prepulse inhibition (PPI, also sensorimotor gating) is the reduction in the ASR
that occurs when a weak stimulus (prepulse) precedes a startling stimulus
with interstimulus intervals between 30 and 500 ms (see Figure 1.8.).
Typically, 50-80% response inhibition has been reported. Besides acoustic
prepulses, also tactile and visual prepulses can be used to inhibit the ASR
(Blumenthal and Gescheider 1987; Campeau and Davis 1995).
PPI is increased with increasing prepulse intensity (Blumenthal 1995).
The optimal interstimulus interval (ISI) between the prepulse and the startle
stimulus is 120 ms in humans (Graham and Murray 1977) and PPI fades
gradually till it is absent at 500 ms (Hoffman and Searle 1968). Inhibition is
not affected when paired prepulses are presented instead of a single pulse
(Blumenthal 1995). PPI shows high test-retest reliability in humans
(Schwarzkopf et al 1993). However, PPI has been shown to be enhanced if a
subject attends to a prepulse (Ison and Ashkenazi 1980; Filion et al 1993;
Blumenthal and Flaten 1994; Jennings et al 1996). In this respect, Koch
(1999) concluded that attentional mechanisms affect PPI at the perceptual
level, whereas higher levels of stimulus processing (cognitive processes) are
protected by the gating mechanism. It has been argued by Swerdlow et al
(2000) that such effects of attentional mechanisms on PPI only occur with
longer ISIs (>120 ms) between the prepulse and startle (see also Filion et al
1998). Besides decreasing the ASR, a prepulse has also been found to
potentiate ASR. This phenomenon of prepulse facilitation (PPF) is still very
elusive. It is not clear whether inhibition and facilitation can be considered as
two sides of one continuum or two completely different and independent
processes. Ison et al (1990) have proposed that stimulus anticipation focuses
excitatory and inhibitory processes simultaneously on different ASR pathways
in human subjects: inhibition central and excitation peripheral. Reijmers and
Peeters (1994b) have also suggested that PPI and PPF are not mediated by
the same neural system.
Figure 1.8.
Prepulse inhibition: Paradigm
Trial 1: With a startle pulse
alone, a large ASR is found
Trial 2: When a prepulse
precedes the startle pulse,
the ASR is inhibited
(Adapted from Swerdlow and
Geyer 1998)
PPI is disturbed in schizophrenic patients (Braff et al 1978, 1992). The
facilitation of the ASR latency that normally occurs with a prepulse was still
intact in patients. Therefore, it has been suggested by Braff et al (1992b) that
the PPI deficit in patients is not due to a failure in stimulus detection and that
the deficit is centrally mediated. Subjects with schizotypal personality
disorder and asymptomatic first-degree relatives of schizophrenic patients
19

have deficits in PPI as well, which has been suggested to support the
importance of PPI as a biological marker for schizophrenia spectrum disorders
(Cadenhead et al 1993, 1999).
Besides in schizophrenic patients, PPI deficits have also been reported
in obsessive-compulsive disorder patients (Swerdlow et al 1993). Corticostriato-pallido-pontine
circuitry dysfunctions have been implicated in PPI
deficits, as will be discussed later. Thus, it can be expected that certain
patients with disorders in this brain circuitry would also show a PPI decrease
compared to healthy subjects. Indeed, Swerdlow et al (1995) have also found
a PPI disruption in patients with Huntington's disease and they identify the
striatum and striatopallidal GABAergic efferent circuitry as critical substrates
for the PPI decrease. Furthermore, it has also been shown that subjects
comorbid for attention-deficit hyperactivity disorder (ADHD) and a tic disorder
(Tourette's syndrome) have significantly reduced PPI, compared to controls
and subjects with ADHD alone (Castellanos et al 1996). The authors have
suggested that deficient pallidal inhibition plays a role in this PPI reduction.
A significant correlation between deficits in PPI and thought disorder
(Roschach-derived thought disturbance measures) have been reported
recently within groups of schizophrenic patients (Perry and Braff 1994; Perry
et al 1999).
Thought disorder refers to problems in the way that a person with
schizophrenia processes and organizes thoughts. For example, the person
may be unable to connect thoughts into logical sequences. Racing thoughts
come and go so rapidly that it is not possible to catch them. Because
thinking is disorganized and fragmented, the ill persons' speech is often
incoherent and illogical. Thought disorder is frequently accompanied by
inappropriate emotional responses: words and mood do not appear in tune
with each other. The result may be something like laughing when speaking
of somber or frightening events.
George: "I can remember having thought patterns when I was really sick
where it seemed like listening to 10 different radio stations that weren't
quite on the station. I would get jumbled up little bits of each one of them
and it was all disjointed and it didn't make any sense. It was hard to
concentrate and figure out the simplest things like what to have for
breakfast or how to get to work." (Schizophrenia: A Handbook for Families)
Also, correlations between PPI deficits and psychotic symptoms (Braff et al
1999; Weike et al 2000) and distractibility (Karper et al 1996) were found in
patients. Patients receiving typical antipsychotics showed less PPI with 30 ms
and 60 ms prepulse trials than control subjects (Kumari et al 1999).
Interestingly, a normalization of PPI was observed by the atypical
antipsychotic clozapine (Kumari et al 1999).
1.2.2.3. PPI in rats
The ASR in rats is often assessed by means of the whole body response (see
Figure 1.9. for the startle box). PPI is maximal at an interstimulus interval
(ISI) of 100 ms (Ison et al 1973) and at prepulse durations of 10-20 ms
(Reijmers and Peeters 1994b). PPI is decreased with a 500 ms ISI between
the startle pulse and prepulse as compared to an ISI of 100 ms (Ellenbroek et
al 1999). Reijmers and Peeters (1994b) have observed PPF with larger ISIs
(>800 ms). Furthermore, PPI increases with increasing prepulse intensity
(Reijmers and Peeters 1994b). PPI is thought to be a pre-attentional process
20

as it appears on the initial pairing of the prepulse and the pulse (Wu et al
1984). This also suggests that PPI is not learned (Swerdlow et al 2000). This
does not preclude the possibility that attentional processes (Filion et al 1998;
Koch 1999) might modulate PPI. PPI in rats has been shown to decline across
trials if prepulses are close to detection threshold. Gewirtz and Davis (1995)
have proposed that this could be due to a reduction in prepulse detection due
to a decrease in attention across trials. However, it is still illusive whether
such effects are due to attentional processes or changes in generalized
arousal (Filion et al 1998). Experience with or prior exposure to startling
stimuli has been shown to enhance the inhibitory effects of visual and
acoustic prepulses (Ison et al 1973). These authors have suggested that this
effect could reflect an increase in a non-specific state of alertness or arousal.
Figure 1.9.
Prepulse inhibition:
Startle reactivity box
(San Diego Instruments)
1.2.2.4. Neural substrate of PPI
The neural substrate implicated in PPI is referred to as the cortico-striatopallido-pontine
circuitry (see Figure 1.10.) (For reviews: Swerdlow et al
1992a; Swerdlow 1996; Koch and Schnitzler 1997; Swerdlow and Geyer
1998; Koch 1999; Swerdlow et al 2000). The pendunculopontine nucleus of
the tegmentum (PPTg) directly innervates the caudal pontine reticular nucleus
(PnC) that has been found to be responsible for the elicitation of the ASR
(Davis et al 1982). Electrolytic or quinolinic acid lesions of the PPTg and
infusion of the GABA-A agonist muscimol into the PPTg eliminate PPI in rats
(Swerdlow and Geyer 1993b; Kodsi and Swerdlow 1997). In turn, the PPTg is
innervated by the ventral pallidum (VP) via a GABAergic mechanism and by
the superior colliculus (SC, receives inputs from different sensory modalities).
Lesioning of the inferior colliculus (IC), a structure that innervates the SC,
has also been shown to disrupt PPI (Leitner and Cohen 1985). Lesions of the
basolateral amygdala (BLA) reduce PPI (Decker et al 1995; Wan and
Swerdlow 1997) via the projection to the VP (Wan and Swerdlow 1997).
Several glutamatergic fibers from the hippocampus (HPC), medial prefrontal
cortex (mPFC), amygdala and cingulate gyrus and DA fibers from the VTA all
converge on the nucleus accumbens (NAC). A reduction in PPI is observed
after quinolinic acid lesions of this center of convergence (Kodsi and Swerdlow
1994). Experimental manipulation of structures projecting to the NAC such as
the mPFC and HPC have also been found to affect PPI. Ibotenic acid lesions of
the HPC in adult rats result in the development of supersensitivity to the PPIdisruptive
effects of the DA agonist apomorphine (Swerdlow et al 1995b). The
ventral HPC is innervated by the medial septum. Stimulation of the medial
septum by injection of the glutamate agonist kainate led to a profound
disturbance of PPI and reduced the ASR amplitude, an effect that could be
attenuated by systemic or intrahippocampal administration of the
21

acetylcholine antagonist scopolamine (Koch 1996). However, lesions of the
medial septum, made by the neurotoxin AMPA, did not affect PPI (Koch
1996). In sum, these findings indicate that activation of the
septohippocampal system reduces PPI. The role of the dorsal striatum
(caudate-putamen or CPu) has not been investigated as extensive as the role
of the ventral striatum (NAC). The reduction in DA in the dorsal striatum in
both lesioned rats and Parkinson patients results in increased sensitivity to
the PPI-disruptive effects of the DA agonist apomorphine (respectively,
Swerdlow et al 1986 and Morton et al 1995). Furthermore, a lesion study
(Kodsi and Swerdlow 1995) showed that the caudodorsal and not the
rostrodorsal or middorsal striatum is involved in PPI. They have suggested
that the caudodorsal striatum mediates PPI via the GABAergic pathway to the
caudal dorsal pallidum that innervates the PPTg. Blockade of neuronal
transmission by tetratoxin (TTX) within the medial geniculate body (MGB) of
the thalamus has been found to reduce PPI (Zhang et al 1999). The authors
propose that auditory signals relayed through the MGB might activate
feedback inhibition of subsequent signals involving GABA receptors. Finally,
lesioning of the mPFC has been found to increase the sensitivity to the
apomorphine-induced disruption of PPI (Swerdlow et al 1995a). Recently, also
attenuation in PPI has been reported following cytotoxic lesions of the mPFC
(Yee 2000). It has been suggested that reduced mPFC function could disrupt
PPI via disinhibition of descending glutamatergic fibers, which results in
subcortical increases in DA transmission in the NAC. This assumption has
been corroborated by the finding that local injections of the GABA-A channel
blocker picrotoxin into the mPFC has been found to reduce PPI, an effect that
could be prevented by systemic pretreatment with the DA antagonist
haloperidol (Japha and Koch 1999). These data also suggest a role for mPFC
GABA receptors in these PPI disruptive effects.
S
IC
22
mPFC
BLA
RN
+
5-HT
SC
cochlear root
neurons
VTA
DA
vHPC
+
ACH
DA
+
+
VP
PPTg
+
_ _
+
_
PnC
NAC
ACH
+
CDS
_
_ CDP
motor
neurons
mSEPTUM
dHPC
ASR
Figure 1.10. Prepulse inhibition:
Circuitry
(BLA=basolateral amygdala;
CDP=caudodorsal pallidum;
CDS=caudodorsal striatum;
dHPC=dorsal hippocampus;
IC=inferior colliculus; NAC=nucleus
accumbens; mPFC=medial prefrontal
cortex; mSEPTUM=medial septum;
PPTg=pendunculopontine tegmental
nucleus; PnC= caudal pontine
reticular nucleus; RN=raphe nuclei;
SC=superior colliculus; vHPC=ventral
hippocampus; VP=ventral pallidum;
VTA=vental tegmental area.
Neurotransmitters:
CH=acetylcholine; DA=dopamine;
- =γ-Amino-butyric acid;
+ =glutamate; 5-HT=5-Hydroxytryptamine
[serotonin])
(Adapted from Koch 1999)

1.2.2.5. Pharmacology of PPI
1. Dopamine Effects of dopamine on PPI are presented in Table 1.1. Swerdlow
et al (2000) have concluded that the largest degree of cross-species
homology in the neural regulation of PPI is found in the DA system. DA
agonists have been found to reduce PPI in both human subjects and in rats
(Mansbach et al 1988; Swerdlow et al 1990, 1992a, 1996; Rigdon et al 1990;
Young et al 1991; Campeau and Davis 1995; Ott and Mandel 1995; Hutchison
and Swift 1999; Abduljawad et al 1999; Sills 1999; Wadenberg et al 2000).
This effect has been linked to a hyperactivity of DA at NAC D2 receptors
(Swerdlow et al 1991; Wan and Swerdlow 1993; Wan et al 1994; Caine et al
1995, Varty and Higgens 1998; Ralph et al 1999) and has been shown to be
only slightly NAC core/shell site-specific with a small predominance of core D2
effects (Wan et al 1994). Zhang et al (2000) have found an increase in DA
overflow in the NAC (using microdialysis) following administration of
amphetamine (SC) that showed a reverse relationship over time with the
amount of PPI. Furthermore, it has been suggested that D1 and D2 receptors
may interact in the regulation of PPI (Peng et al 1990; Schwarzkopf et al
1993; Hoffman and Donovan 1994; Wan et al 1996b). DA infusion in the
anteromedial and not the posterolateral striatum has been found to disrupt
PPI (Swerdlow et al 1992). Finally, a decrease in PFC DA activity also
decreases PPI. This has been shown by depleting medial PFC DA by infusion
of 6-hydroxydopamine (6-OHDA) (Bubser and Koch 1994; Koch and Bubser
1994) and by infusion of D1 and D2 antagonists (respectively, SCH 23390
and sulpiride) in the medial PFC and orbital PFC (Ellenbroek et al 1995;
Zavitsanou et al 1999). These effects have been suggested to result from
disinhibition of the excitatory glutamatergic afferents projecting from the PFC
to the VTA and NAC, which results in subcortical increases in DA transmission
in the NAC.
2. Other neurotransmitters Many researchers have found a PPI reduction
following systemic injections of non-competitive (N-methyl-D-aspartate)
NMDA receptor antagonists that are known to reduce the glutamate activity in
the brain (Geyer et al 1989; Mansbach 1991; Mansbach and Geyer 1991;
Hoffman et al 1993; Bakshi et al 1994; Johansson et al 1994; Wiley 1994;
Reijmers et al 1995). Local effects in the NAC or ventral subiculum (vSUB) do
not mediate the systemic effects, since the effects are opposite. First, PPI is
disrupted by intra-NAC infusion of glutamate (Swerdlow et al 1992b) or
glutamate agonists such as NMDA (Reijmers et al 1995; Wan et al 1995b)
and AMPA (Wan et al 1995a). Secondly, PPI is also disrupted by NMDA
infusion into the vSUB and this effect is reversed by coinfusion of the NMDA
antagonist D,L-amino-5-phosphono-valeric acid (APV) (Wan et al 1996a).
Also, no change in PPI was produced by the NMDA antagonist dizocilpine into
the NAC, ventral hippocampus, or dorsomedial thalamus. In contrast,
dizocilpine significantly decreased PPI after infusion into the amygdala or
dorsal hippocampus and a trend toward PPI disruption was observed with
administration into the mPFC (Bakshi and Geyer 1998). In short, local effects
in the amygdala or dorsal hippocampus probably mediate systemic effects of
non-competitive NMDA antagonists.
23

Table 1.1. Dopaminergic effects on PPI
Species area PPI↓ Reversal reference
DA
Rat ⎯ apomorphine (D1/2 ag)
amphetamine (DA ag)
haloperidol (DA anta) Mansbach et al '88
Rat ⎯ amphetamine (DA ag) DA lesion (6-OHDA) Swerdlow et al '90
Rat ⎯ apomorphine (D1/2 ag) Rigdon et al '90
Rat ⎯ apomorphine (D1/2-ag) Young et al '91
Rat ⎯ apomorphine (D1/2 ag)
auditory and visual PP
Campeau and
Davis '95
Rat ⎯ amphetamine (DA ag) Ott and Mandel '95
Rat ⎯ apomorphine (D1/2 ag)
haloperidol (DA anta)
risperidon (D2/5-HT2
anta)
Rat ⎯ amphetamine (DA ag) Sills '99
Swerdlow et al '96
Human ⎯ amphetamine (DA ag) Hutchison and
Swift '99
Human ⎯ bromocriptine (D2 ag) haloperidol (DA anta) Abduljawad et al
'99
Rat ⎯ amphetamine (DA ag) Zhang et al 2000
Rat ⎯ apomorphine (D1/2 ag)
DA RECEPTOR
SUBTYPES
Rat ⎯ quinpirole (D2/D3 ag)
SKF 38392 (D1 ag)
subthreshold
combination
amoxapine (D2/5-HT2
anta)
Rat ⎯ apomorphine (DA ag) raclopride (D2 anta)
spiperone (D2 anta)
SCH 23390 (D1 anta)
clozapine (low dose)
clozapine (high
dose)
Rat ⎯ apomorphine (DA ag) haloperidol (D2 anta)
SCH 23390 (D1 anta)
combination:
potentiation
Rat ⎯ apomorphine (DA ag) eticlopride (D2 anta)
SCH 23390 (D1 anta)
Rat ⎯ quinpirole (D2/3 ag)
7-OH-DPAT (D2/3 ag)
apomorphine (D1/2 ag)
Rat ⎯ (+)-PF 128907 (D3 ag)
Rat ⎯ Subthreshold
combination of
quinpirole (D2/D3 ag)
and SKF 38392 (D1 ag)
24
SKF 82958 (D1 ag)
haloperidol (DA anta)
UH 232 (DA anta)
equal D3 affinity,
haloperidol (>D2 aff)
raclopride (D2 anta)
SCH 23390 (D1 anta)
Wadenberg et al
2000
Peng et al '90
Swerdlow et al '91
Schwarzkopf et al
'93
Hoffman and
Donovan '94
Caine et al '95
Bristow et al '96
Wan et al '96

Species area PPI↓ Reversal reference
Rat ⎯ quinpirole (D2/3 ag)
7-OH-DPAT (D2/3 ag)
PD 128907 (D2/D3 ag)
quinpirole (D2/3 ag)
apomorphine (D1/2 ag)
bromocriptine (D2
ag)
SKF 38393 (D1/5 ag)
cocaine (DA ↑)
GBR 12909 (DA ↑)
Knock-out
mice
⎯ amphetamine (DA ag)
D2 (-/-) D2 (+/+)
D3 (-/-) D3 (+/+)
D4 (-/-) D4 (+/+)
raclopride (D2/3 anta)
WAY 100135 (5-
HT1A anta)
domperidone (D2
anta periphery)
Varty and
Higgens'98
Ralph et al '99
Rat ⎯ 7-OH-DPAT (D2/3 ag) Ellenbroek et al '99
CLOZAPINE AND D4
Rat ⎯ apomorphine (DA ag)
Rat ⎯ amphetamine (DA ag)
clozapine
seroquel (D2/5-HT2
anta)
clozapine
NRA 0045 (D4 anta)
haloperidol
Rat ⎯ apomorphine (DA ag) clozapine
CP-293,019 (D4 anta)
U-101,387 (D4 anta)
L-745,870 (D4 anta)
Swerdlow et al '94
Okuyama et al '97
Mansbach et al '98
Rat ⎯ apomorphine (DA ag) clozapine Okuyama et al '99
LOCAL EFFECTS
Rat VMT apomorphine (DA ag) Young et al '95
Rat mPFC DA lesion (6-OHDA) Bubser and
Koch'94
Rat mPFC DA lesion (6-OHDA) haloperidol (DA anta) Koch and
Bubser'94
Rat mPFC SCH 39166 (D1-anta)
sulpiride (D2-anta)
Rat ORB PFC SCH 39166 (D1-anta)
sulpiride (D2-anta)
Rat NAC
AMS
amygdala
ORB PFC
PLS
Ellenbroek et al '96
Zavitsanou et al
'99
DA Swerdlow et al '92
Rat NAC DA Swerdlow et al '90
Rat NAC quinpirole (D2 ag) haloperidol Wan and Swerdlow
'93
Rat NAC quinpirole Wan et al '94
6-OHDA EFFECTS
Rat ⎯ apomorphine (DA ag):
lesioned > sham
Effects are not significant when printed in bold-italic
Schwarzkopf et al
'92
(ag=agonist; AMS=anteromedial striatum; anta=antagonist; DA=dopamine;
mPFC=medial prefrontal cortex; NAC=nucleus accumbens; ORB PFC=orbital
prefrontal cortex; PLS=posterolateral striatum; VMT=ventromedial thalamus)
25

Besides dopamine and glutamate also the serotonergic and cholinergic
systems have been implicated in PPI deficits. PPI reduction has been
observed after stimulation of 5-HT1 and 5-HT2 receptors (Rigdon and
Weatherspoon 1992; Sipes and Geyer 1994, 1997) in rats. Smoking in
deprived healthy smokers has been found to enhance PPI for a short period of
time (Kumari et al 1996), whereas smoking withdrawal after nicotine
dependence decreased PPI in healthy subjects (Kumari and Gray 1999).
Finally, several researchers have shown that the muscarinic acetylcholine
antagonist scopolamine can decrease PPI (Wu et al 1993; Fendt and Koch
1999; Jones and Shannon 2000).
3. Non-pharmacological manipulations: Neurodevelopmental animal models
for schizophrenia such as isolation rearing and maternal deprivation have also
been shown to reduce PPI (Wilkinson et al 1994; Bristow et al 1995; Varty
and Higgens 1995; Bakshi et al 1998; Ellenbroek et al 1998; Varty and Geyer
1998; Varty et al 1999a; 1999b). Finally, differences between rat and mice
strains in PPI and drug-induced changes in PPI have been found (Rigdon
1990; Ellenbroek et al 1995; Logue et al 1997; Paylor and Crawley 1997;
Swerdlow 1998).
1.2.3. P50 GATING PARADIGM
1.2.3.1. EEG and auditory evoked potentials (AEPs)
The human brain produces electrical activity associated with currents
generated across neuronal membranes. Some of this electrical activity is
conducted to the scalp. An electroencephalogram (EEG) is a recording of this
electrical activity obtained from electrodes placed on the scalp (Duffy et al
1989).
Stimulation of sensory receptors can produce waves of positive and
negative deflections in the EEG, called evoked potentials (EPs). EPs are waves
in the EEG that result from a sensory event such as a light or a click. Most
EPs cannot be clearly seen on an EEG record, because they are generally of
low amplitude relative to the normal background brain wave activity. Thus, it
is necessary to average the electrical activity over multiple presentations of
the same stimulus. Since the background EEG activity will be random relative
to the sensory event, the EP will be seen clearly after averaging of a few trials
(Kolb and Whishaw 1990). Particular EP deflections are usually referred to in
terms of their latency, or how long it takes a deflection to appear in the EP
after stimulus onset, and amplitude, usually in microvolts. "N" refers to a
negative deflection and "P" to a positive deflection. A deflection, which is
regularly observed in an experimental paradigm, is often called a component
of the EP, typically measured relative to a peak in the waveform.
Auditory evoked potentials (AEPs) (see Figure 1.11.) are responses
following auditory stimuli. AEP components can be divided into three
categories: early (50
ms) components (Squires and Ollo, 1986). Furthermore, EP components are
also categorized into two general categories, exogenous and endogenous.
Exogenous components such as the P50 and N100 are primarily responsive to
stimulus properties, such as duration, intensity, and frequency and occur
whether or not the subject is paying attention to the stimuli. Abnormalities in
exogenous components are consistent with abnormalities in the sensory and
perceptual processing of stimuli. Endogenous components such as the N200
26

and P300 are affected by psychological factors, such as task relevance and
expectancies. Abnormalities of endogenous components may reflect
abnormalities of neural structures involved in higher cognitive functions, such
as attention and memory. In short, midlatency components such as the P50
AEP component can be regarded as reflecting a pre-attentive process,
whereas late-occurring waves such as the P300 are suggested to reflect the
attentional processing of incoming stimuli.
I
LL
MGB
SO
CN
Auditory
stimulus (S)
AN
amplifie
Signal
averager
60 dBSL
click
Stimulus onset
Cz+(A-)
2 4 6 8 10 ms
0.1 µV
ongoing EEG
Brainstem auditory
evoked potential
(BAEP)
Auditory evoked potential (AEP)
(P 50)
Figure 1.11. AEP gating: Auditory evoked potentials
Time (ms)
(Adapted from Nuechterlein and Dawson 1994) (AN=auditory nerve;
CN=cochlear nucleus, IC=inferior colliculus; LL=lateral lemniscus;
MGB=medial geniculate body of the thalamus; SO=superior olivary nuclei)
By measuring EPs to stimuli, it is possible to reach conclusions about the
functioning of the different sensory pathways and the circuitry's involved in
27

the potential modulation (inhibition or excitation) of the sensory information
processing. In clinical practice, visual, auditory, and somatosensory stimuli
are commonly used to elicit EPs that provide information regarding the
integrity of sensory pathways within the nervous system (Chiappa 1983). EPs
have several advantages: they have a high temporal resolution (within the
ms time-range), are non-invasive and non-hazardous and hence averaging of
repeated presentations of stimuli can be used to enhance the signal-to-noise
ratio. A disadvantage of EPs as an imaging modality is their relatively poor
spatial resolution, and the consequent difficulty in defining their source(s)
within the brain. Based on electrical source analysis,
magnetoencephalographic (MEG) source analysis and lesion studies, it has
been suggested that the sources of the N100 and P200 include temporal lobe
structures (Naatanen and Picton 1987; Vaughan 1988), whereas the P300 is
likely to have multiple brain electrical sources (Halgren 1986). It has been
postulated that the P50 arises in medial temporal lobe structures (Bickford-
Wimer et al; Adler et al 1985). This has been suggested from surface
mapping studies (Woods and Wolpaw 1982). Furthermore, MEG with
correlated resonance imaging suggests a superficial location in the temporal
planum (Reite et al 1988). Larger P50 waves in patients with bilateral
temporal cortex strokes have been found that argue against a cortical
location, whereas lesions that extend to the hippocampus have been found to
significantly diminish P50 amplitude that suggests a hippocampal origin
(Woods et al 1984, 1987).
1.2.3.2. P50 gating in human subjects: an inhibitory process
In the sensory gating paradigm, an auditory click (S1) is presented to a
subject, eliciting a positive deflection at 50 ms after stimulus onset. This
deflection is referred to as the P50 component. After a brief interval, about
500 ms, a second click (S2) elicits a much smaller P50 in normal control
subjects, who are said to show normal gating. The ratio of the amplitude of
the second click to the first click is normally used to measure the degree of
gating in a subject.
28
Figure 1.12.
AEP gating:
Illustration P50 gating
Deficit in a
schizophrenic patient
versus a healthy
subject. The first
waveform is the
response to S1 and the
second waveform is
the response to S2.
(Adapted from Adler et
al 1998)

The reduction in P50 amplitude to the second click is much less pronounced in
schizophrenic subjects (see the illustration in Figure 1.12.). In other words,
they have a failure in gating (Adler et al 1982; Freedman et al 1983; Judd et
al 1992). Ratios below 40% have been reported to be typical of normal
subjects, and ratios above 40% are typical of schizophrenic patients (Siegel
et al 1984; Waldo et al 1991). The P50 gating deficit best discriminates
between control and schizophrenic patients at the vertex electrode (central
zone or Cz, Nagamoto et al 1991). Furthermore, P50 gating disturbances in
schizophrenic patients have only been found at the 150 and 500 ms ISIs and
not at the 75 ms ISI (Nagamoto et al 1989). Typical antipsychotic medication
such as haloperidol does not eliminate the sensory gating differences between
control and schizophrenic subjects (Freedman et al 1983; Adler et al 1990).
In contrast, the atypical antipsychotic clozapine improves P50 gating to
normal levels in patients (Nagamoto et al 1996, 1999; Light et al 2000).
The neurophysiological defect in sensory gating may relate to a
disorder in sustained attention in schizophrenia as suggested by Cullum et al
(1993). They have found that the time to complete the digit cancellation test
(a measure of sustained attention) correlated negatively with the gating in
patients. Auditory sensory processing defects in schizophrenia appear to be
independent of negative symptoms (Adler et al 1990). Finally, some
paradoxical results have been obtained by Jin et al (1998): patients reporting
perceptual anomalies exhibited normal gating, whereas patients who did not
report perceptual anomalies showed the abnormal P50 ratios (Jin et al 1998).
Light and Braff (2000) commented on these findings by arguing that selfreports
in schizophrenic patients have considerable limitations (Light and
Braff 2000).
Diminished sensory gating has also been reported to occur in about
half of the first-degree relatives of schizophrenic patients (Siegel et al 1984).
The likelihood of P50 gating abnormality increases as a function of both family
relationship and symptomatology (Waldo et al 1988, 1995). Also, subjects
with schizotypal personality disorder have reduced P50 gating (Cadenhead et
al 2000). A decrease in sensory gating is found in other severely ill psychiatric
patients as well, such as acutely manic patients during psychosis (Franks et al
1983). As soon as their clinical condition improved following treatment with
lithium carbonate, also the gating was normalized in these patients. Since
such an improvement was not seen in medicated schizophrenics, gating
deficits have been considered as a trait characteristic in schizophrenic
patients (Baker et al 1987). Recently, taken into account the gating
improvement with the atypical antipsychotic clozapine in schizophrenic
patients (Nagamoto et al 1996, 1999; Light et al 2000), this consideration
should be reevaluated.
Besides the observed decrease in gating, schizophrenic patients also
show a significantly smaller amplitude and latency of the P50 in responses to
unpaired stimuli compared to controls (Adler et al 1982; Jin et al 1997). Jin et
al (1997) have concluded that this reduction in the initial P50 response to S1
(conditioning amplitude or CAMP) could to be an important contributor to the
decrease in gating. They have found that the temporal variability (jitter) in S1
P50 was significantly greater in schizophrenics than in controls and proposed
that jitter may contribute to central inhibitory processes. According to Jin and
colleagues (Jin et al 1997; Patterson et al 2000) this 'jitter' phenomenon
could be linked to the concept of 'occlusion' described by Adler et al (1982):
when a neuronal population is hyperactive, its constant background discharge
makes it less likely, that the majority of the neurons will respond
synchronously to the stimulus being studied. This will consequently lead to
29

smaller amplitudes. Adler et al (1982) have suggested that this hyperactivity
is due to a lack of functional inhibitory input.
1.2.3.3. P50 gating in human subjects: alternative explanations
Besides inhibitory processes, alternative explanations have been given for
gating, such as refractoriness (1), neuronal or receptor fatigue (2) and
stimulus quality adaptation due to a decrease in attention (3). First, Calloway
(1973) introduced the concept of 'recovery cycles', occurring with very short
ISIs between two stimuli (such as 10 ms): aggregates of cells show a short
period of unresponsiveness following activation that results from membrane
depolarization (also called refractory period). Several authors suggested this
to be an unlikely explanation for human P50 gating, since recovery of
neuronal excitability has been shown to occur within 2-3 ms (Koester et al
1991) and long-lasting refractoriness rarely exceed 500 ms in duration (Adler
et al 1982). Moreover, the majority of the refractory period has been shown
to result from inhibitory mechanisms (Eccles 1969). Secondly, neuronal or
receptor fatigue could cause the decrement of the response to S2. However,
the fact that gating is reduced at ISIs shorter than 100 ms in comparison to
the 500 ms ISI in normal subjects is not in agreement with this suggestion
(Freedman et al 1983; Franks et al 1983). Reduced gating at shorter ISIs
suggests that inhibitory processes, rather than fatigue, are responsible for the
gating at longer ISIs (Franks et al 1983). The third explanation for gating is
'stimulus quality adaptation due to a decrease in attention'. Several
researchers have considered P50 gating to be a pre-attentional phenomenon:
an attention decrease observed during repeated trials did not seem to cause a
decrement in P50 gating in healthy subjects (Freedman et al 1983) and
cortical N40-N50 gating was still observed in anesthetized animals (Bickford-
Wimer et al 1990). Also, gating is not reduced during nonrapid eye movement
(NREM) sleep in rats (Van Luijtelaar et al 1998). Additionally, White and Yee
(1997) have found the N100 to be responsive to attentional manipulation,
whereas the P50 was not affected. Finally, changes in concentration
(measured by the serial subtraction test) have been found not to affect gating
(Waldo and Freedman 1986). Indeed, these studies suggest that attentional
processes are not involved in gating. However, Jin and Potkin (1996) have
shown that gating was reduced in a visual interference condition due to a
decrease in P50 amplitude to S1 and White and Yee (1997) have found P50
suppression to be sensitive to an acute stressor.
1.2.3.4. Repetitive stimulation and the interstimulus interval (ISI)
It has been found in human subjects that the amount of sensory gating is
dependent on repetitive stimulation and the interstimulus interval (ISI) (Starr
et al 1997; Boutros and Belger 1999; Adler et al 1982; Freedman et al 1983).
When 50 or so stimuli are given, the AEP for the first half of the stimuli
is generally larger than the AEP for the second half. Several authors have
suggested that sensory gating can change during a recording session (Franks
et al 1983; Siegel et al 1984; Lamberti et al 1993; Clementz et al 1997).
Lamberti et al (1993) have found a higher suppression during the first 30
click pairs compared to the last 30 pairs during a 120 trial session. They have
shown that these effects on gating were due to a gradual reduction of P50
amplitude to the S1 (Lamberti et al 1993). Controversial results have been
reported with respect to the effects on the amplitude to S2: Lamberti et al
(1993) have found an increase, whereas Naber et al (1992) reported a
30

decrease over the recording session. Clementz et al (1997) have found a
more pronounced difference in suppression between schizophrenic patients
and controls during the first than during the second block of trials. Cacace et
al (1990) have noted that the amplitude of the P50 decreased as the number
of summation increased. Also, Starr et al (1997) reported a decrease of the
P50 with stimulus sequence and an increase in the human P50 after a target
stimulus. In this respect, Boutros et al (1995) have distinguished between
two types of gating. The first type is the more traditionally used concept:
'gating out' or decreased responding to incoming irrelevant stimuli (gating is
enhanced). The second type, 'gating in', when a novel stimulus is presented
or a change occurs in ongoing stimuli (gating is decreased). In a recent paper
by Boutros and Belger (1999), it has been suggested that the human P50 EP
is sensitive to the effects of stimulus repetition and stimulus change:
respectively 'gating out' and 'gating in'. Interestingly, Boutros et al. (1999)
have found that schizophrenic patients have difficulty in 'gating out' irrelevant
input and 'gating in' relevant input at both the early pre-attentive stage (P50)
and at the later early-attentive stage (N100) as well.
Several authors have found that the amount of sensory gating is
dependent on the interstimulus interval (ISI). Adler et al (1982) and
Freedman et al (1983) have found a decrease in sensory gating with
increasing ISIs (> 1 s), both in a population of untreated schizophrenic
patients and healthy controls. These authors noted also that the changes in
P50 gating are mainly due to changes in the amplitude of the AEP towards
S2. Zouridakis and Boutros (1992) have also found that the amplitude of the
P50 towards the S2 shows a progressive recovery with longer ISIs, thereby
decreasing gating. Furthermore, Adler et al (1982) have found facilitation
with the 50 ms ISI and an approach to recovery to initial values with the 6
sec ISI in healthy human subjects. The full recovery time of the P50
amplitude has been estimated at 8 s (Zouridakis and Boutros 1992).
Nagamoto et al (1989) investigated short (500, 150 and 75 ms) ISIs. P50
gating did occur at all three ISIs in the control group, however, the ISI was
critical for the schizophrenics. More specifically, P50 gating was disturbed in
patients at an ISI of 150 and 500 ms, not at an ISI of 75 ms.
1.2.3.5. AEP gating in rats
The EEG activity in rats is directly recorded from the brain (epidural
electrodes), whereas in human subjects the EEG is recorded from the scalp.
Therefore, an advantage of rat AEPs is the better signal/noise ratio. One of
the problems is that different groups or researchers report not always the
same components of an AEP and a standardized electrode system such as the
10-20 system in humans is lacking. The morphology of the AEP is not only
dependent on the stimulus properties, but also on the localization of the EEG
electrodes, whether a monopolar or bipolar recording is made and on the
localization of the reference and ground electrode. Absence of a standardized
way of measuring between groups hampers comparisons of different studies
that currently still describe different components of the rat’s AEP (Adler et al
1986; Miyazato et al 1996). Furthermore, it is not immediately clear what the
equivalent is for the human P50 in the rat. Some (Miyazato et al 1996)
propose an early component (the P13), others suggest that the cortical N40-
N50 is the equivalent (Adler et al 1986). The later authors also propose that
the rat P20-N40 wave, recorded from the cornu ammonis (CA) 3 and 4
regions of the hippocampus (HPC), shows suppression of response to
repeated stimuli similar to that of the human P50 wave.
31

1.2.3.6. Neural substrate of AEP gating
Especially the hippocampus (HPC) seems to be a very important brain area in
AEP gating (for review: Adler et al 1998). The HPC is divided into the dentate
gyrus (DG), which contains the granule cells, and areas CA1-CA4, which
contain the pyramidal cells (see Figure 1.13.). It also has contiguous
neocortical areas that are closely related to its functioning: the subicular
complex and the entorhinal cortex (EC). The EC receives polymodal sensory
input from association areas throughout the neocortex. Directly through the
perforant pathway (PP) and indirectly through the DG mossy fiber (MF)
projections, the EC conveys this sensory information to the pyramidal cells of
the CA3 region (for review also see Amaral and Witter 1995). Besides the
cortical input via the primary lemniscal pathway, the CA3 region also receives
inputs from non-lemniscal pathways via the brainstem. Brain stem neurons
project directly to CA3 from the noradrenergic locus coeruleus (LC) and the
serotonergic raphe nucleus (RN). Additionally, the brain stem reticular
formation influences the HPC indirectly, via the cholinergic projection from the
medial septum (Bickford et al 1993). Finally, the CA3 region projects to CA1
via the Schaffer collaterals (Ishizuka et al 1990) that reach the subicular
complex. A second target of the CA3 is the lateral septum (Swanson 1980).
Thus, the CA3 is a major point of convergence for cortical and brainstem
inputs from both the lemniscal and non-lemniscal auditory pathways (see
Figure 1.13.) and this area has been suggested to be a modulator in the
sensory gating process (Bickford-Wimer et al 1990; Miller and Freedman
1995; Stevens et al 1998; Adler et al 1998).
Adler et al (1998) have proposed a model that describes the process
that is suggested to give rise to P50 gating. S1 is thought to activate CA3
pyramidal cells through the PP input from the EC and the granule cell input
from the DG. The cholinergic input from the medial septum is also activated
so that there is a burst of activity in the pyramidal cells (Miller and Freedman
1995). Consequently, a large portion of CA3 pyramidal neurons is thought to
be excited by S1. Then, interneurons in the HPC have been suggested to
inhibit CA3 pyramidal cells during the interclick interval (Miller and Freedman
1995). Adler et al (1998) have speculated that the response to S2 is probably
diminished due to an inhibition of glutamate release from the granule cell MF
synapses and from recurrent pyramidal cell synapses. Therefore, S2 is
thought to excite a much more restricted population of neurons. The authors
propose that GABA could be involved in this inhibition (Adler et al 1998).
Although this is an interesting model for P50 gating, only one study provides
evidence confirming the involvement of GABA in gating. Hershman et al
(1995) have shown that GABA-B antagonists such as CGP-35348 can diminish
gating in the rat hippocampus by increasing the amplitude to S2.
Moxon et al (1999) have studied single-unit neuron firing in response to
auditory clicks. They have found that the response to the clicks was most
pronounced in the brainstem reticular nucleus and the medial septal nucleus,
while relatively few neurons responded in the CA3 and the auditory cortex.
Furthermore, these authors have found support for the hypothesis that
inhibitory gating originates in the non-lemniscal pathway and not in cortical
areas of the rat brain. Brainstem reticular nucleus neurons showed the
greatest gating of local AEPs, while the auditory cortex showed the least.
Gating of the CA3 response was significantly correlated with gating in the
medial septal nucleus and brainstem reticular nucleus, but not the auditory
cortex. In another study, using Fos-immunoreactivity, it has been shown that
besides the medial also the lateral septum is involved in AEP gating (Van
32

Luijtelaar et al unpublished data). As has already been described before
(paragraph 1.1), the VTA sends DA projections to the hippocampal DG, lateral
septum (Swanson 1982) and cortical areas (e.g. EC) (Berger et al 1976;
Björklund and Lindvall 1984; Fuxe et al 1985; Descarries et al 1987). So, a
modulation of gating could take place via these DA fibers to the DG and EC.
EC
Dendate
gyrus
Entorhinal
cortex (EC)
Cortical
association
area
PP
Primary
auditory
cortex
MF
PP
DG
to Subicular complex
DA
DA
Primary
lemniscal
pathway
CA1
VTA
ACH
MF
CA1
CA3
Medial septum
Brainstem RF
IC LL VCN DCN
Figure 1.13. AEP gating: Circuitry
Lateral septum
LC
CA3
NE
Non-lemniscal
pathway
SHP
RN
5-HT
DCN=dorsal cochlear nuclei; DG=dentate gyrus; EC=entorhinal
cortex IC=inferior colliculus; LC=locus ceruleus; LL=lateral
lemniscus; MF=mossy fibers; PP=perforant pathway; RF=reticular
formation; RN=raphe nuclei; SHP=septo-hippocampal pathway;
VCN=ventral cochlear nuclei; Neurotransmitters: ACH=acetylcholine;
DA=dopamine; NE=noradrenaline; 5-HT=5-Hydroxytryptamine
(serotonin) (Adapted from Adler et al 1998)
33

1.2.3.7. Pharmacology of AEP gating
1. Dopamine Effects of DA on AEP gating are presented in Table 1.2. Although
the evidence for the involvement of DA in AEP gating is not as extensive as
for PPI, DA seems to play a modulatory role in AEP gating as well. DA
agonists such as bromocriptine and amphetamine have been found to reduce
P50 gating in healthy human subjects (respectively, Adler et al 1994 and
Light et al 1999). Similar results have been obtained in rats: apomorphine
and amphetamine reduced gating of the cortical N40-N50 component (Adler
et al 1986; Stevens et al 1995, 1996). Also, the gating of the hippocampal
P20-N40 was significantly reduced after amphetamine (Bickford-Wimer et al
1990). The indirect DA agonist amphetamine did not affect gating in neonatal
DA lesioned rats, whereas the direct DA agonist apomorphine reduced gating
in both sham and lesioned animals (Stevens et al 1996). Furthermore,
amphetamine has been proposed to reduce gating through its effects on
alpha- and beta- adrenergic receptors and DA D1 receptors (Stevens et al
1991). This study showed that adrenergic effects were predominantly on the
amplitude to S2 (on the testing amplitude or TAMP), whereas DA effects were
on the amplitude to S1 (the conditioning amplitude or CAMP). The role of DA
activity at D2 receptors is less evident, since amphetamine effects were only
partially blocked by the D2 antagonist sulpiride (Stevens et al 1991) and the
D2/D3 agonist 7-OH-DPAT did not reduce gating (Ellenbroek et al 1999).
Table 1.2. Dopaminergic effects on AEP gating
Species Area Gating↓ Reversal Reference
DA
Rat ⎯ amphetamine (DA ag) Adler et al '86
Rat ⎯ amphetamine (DA ag)
hippocampal gating
haloperidol Bickford-Wimer et
al '90
Human ⎯ bromocriptine (DA-ag) Adler et al '94
Rat ⎯ amphetamine (DA ag) nicotine (blocked by dtubocurarine)
Stevens et al '95
Human ⎯ amphetamine (DA-ag) Light et al '99
Rat
⎯
DA RECEPTOR
SUBTYPES
amphetamine (DA ag) phentolamine (α anta)
timolol (β anta)
SCH 23390 (D1 anta)
sulpiride (D2 anta,
trend)
Stevens et al '91
Rat ⎯ 7-OH-DPAT (D2/3 ag) Ellenbroek et al '99
6-OHDA EFFECTS
Rat ⎯ apomorphine (DA ag):
lesioned = sham
amphetamine (DA ag):
lesioned sham
Effects are not significant when printed in bold- italic.
ag=agonist; anta=antagonist; DA=dopamine.
Stevens et al '96
2. Other neurotransmitters One of the most important neurotransmitter
systems in AEP gating is thought to be the nicotinic cholinergic system (for
review see Adler et al 1998). It has been suggested that heavy smoking in
34

schizophrenics may represent a form of self-medication. Scopolamine and
mecamylamine, which block muscarinic and high affinity nicotinic receptors,
respectively, did not alter the inhibitory gating of the rat hippocampal P20-
N40. However, alpha-bungarotoxin, which blocks a lower affinity population of
nicotinic receptors (alpha-7), did reduce sensory gating (Luntz-Leybman et al
1992). Cholinergic afferents, by activating these alpha-bungarotoxin-sensitive
receptors, may excite inhibitory neurons, which then discharge in prolonged
fashion to produce a long-lasting inhibition of the response of pyramidal
neurons to afferents from the PP (Miller and Freedman 1995). Freedman et al
(1995) have found diminished alpha-bungarotoxin labeling of interneurons in
postmortem samples of hippocampus from schizophrenic patients. However,
nicotine does not appear to have long-lasting therapeutic effects on gating,
probably because of a desensitization of the nicotinergic receptors (Griffith et
al 1993, 1996; Griffith and Freedman 1995). These authors have done
several experiments that provide evidence for the suggestion that
desensitization of the nicotinergic receptors reduce the therapeutic effects of
nicotine. To resensitize the nicotinergic receptors, subjects were allowed to
have a period of NREM sleep (cholinergic neurons cease firing). A short
normalization following NREM sleep was observed in patients. Applying a
nicotine transdermal patch prior to the experiment, however, could prevent
this normalization.
Besides cholinergic and DA effects on AEP gating, a reduction in glutamate
activity in the brain is thought to reduce gating. Non-competitive NMDAreceptor
antagonists such as PCP and MK-801 significantly reduced cortical
and hippocampal gating in rats (Adler et al 1986; Miller et al 1992). Also,
serotonin (5-HT) seems to be involved. Systemic administration of the 5-HT2receptor
antagonist ketanserin reduced sensory gating. In contrast, the 5-
HT2-receptor agonist DOI significantly improved gating. In addition, DOI
antagonized the disruption of gating induced by administration of
amphetamine (Johnson et al 1989).
3. Non-pharmacological manipulations Currently, only one study by Stevens
et al (1997) has reported the effect of isolation rearing on AEP gating in rats.
Socially reared rats showed substantial gating, while isolation-reared rats
failed to gate. The isolation-reared rats were given nicotine bitartrate that
enhanced the gating for 60 min. By contrast, haloperidol failed to normalize
gating in these rats. Gating has also been found to be disrupted in maternally
deprived animals (Ellenbroek et al unpublished data). Interestingly, DBA/2
mice, an inbred strain with reduced hippocampal alpha-7 nicotinergic
receptors, showed hippocampal gating deficits (Stevens and Wear 1997) that
could be normalized with the nicotinic agonist ABT418. Finally, in a previous
study by Van Luijtelaar et al (1998), gating was studied during three different
vigilance states: passive wakefulness, REM and non-REM sleep. Although
significant gating was observed in all three conditions, gating was significantly
reduced during REM sleep as compared to the passive wakefulness state (Van
Luijtelaar et al 1998).
1.2.4. SIMILARITIES AND DIFFERENCES BETWEEN PPI AND AEP GATING
Various similarities and differences have been found between PPI and AEP
gating based on parametric variables, findings in patients, data on the neural
substrate and pharmacological manipulations.
35

1.2.4.1. Similarities
In the early 1990's, it was suggested that both gating measures involve
similar mechanisms (Ellenbroek and Cools 1990; Freedman and Mirsky 1991;
Braff 1993). A general similarity between both processes is that they reflect
long-lasting inhibitory processes in the auditory pathway.
Gating deficits in both PPI and AEP gating in schizophrenic patients
have been suggested to be dependent on genetic factors and have been
referred to as a trait deficit or biological marker for schizophrenia spectrum
disorders. Such suggestions are based on studies in which gating failure was
reported in asymptomatic family members and subjects with schizotypical
personality disorder (Waldo et al 1988, 1995; Cadenhead 1993, 1999, 2000).
Furthermore, both PPI and AEP gating deficits in patients have been found to
normalize with the atypical antipsychotic clozapine, whereas no improvement
was found with typical antipsychotics such as haloperidol (Freedman et al
1983; Adler et al 1990; Nagamoto 1996, 1999; Kumari et al 1999; Light et al
2000)
When comparing the neural substrate of both gating processes based
on rat studies, the septo-hippocampal system seems to be an important brain
area in both PPI (Caine et al 1992; Koch 1996) and AEP gating (Bickford-
Wimer et al 1990; Miller and Freedman 1995; Stevens et al 1998).
Some final common results have been obtained in pharmacological
studies. With respect to pharmacological effects in rats, it has been shown
that systemically injected DA agonists and non-competitive NMDA antagonists
decrease PPI and AEP gating (Mansbach et al 1988; Swerdlow et al 1996;
Adler et al 1986; Bickford-Wimer et al 1990; Stevens et al 1995; Geyer et al
1989; Mansbach et al 1991; Mansbach and Geyer 1991; Adler et al 1986;
Miller et al 1992). In contrast, nicotinergic agents have been found to
temporarily restore PPI and AEP gating deficits (Kumari et al 1996; Stevens
et al 1997; Stevens and Wear 1997).
1.2.4.2. Differences
Lately, there has been increasing evidence that both paradigms differ in many
aspects and it has therefore been suggested that both gating measures might
reflect different inhibitory processes in the brain (Schwarzkopf et al 1993;
Ellenbroek et al 1999). The experimental conditions in both the PPI and AEP
gating paradigm differ in several ways. First, in PPI the output parameter is a
reflex, whereas in AEP gating the EEG/AEP is registered. Secondly, the stimuli
presented in both paradigms differ. Third, inhibition in the PPI paradigm is
maximal at ISIs of 100-120 ms (Graham and Murray 1977; Braff et al 1978)
and reduced at an ISI of 500 ms in healthy subjects (Hoffman and Searle
1968). In normal subjects, AEP gating occurs at ISIs of 75, 150 and 500 ms
and facilitation with the 50 ms ISI (Adler et al 1982; Nagamoto et al 1989).
Moreover, gating is only disturbed at the 150 and 500 ms ISIs in
schizophrenic patients (Nagamoto et al 1989). In contrast, these patients
have a significant reduction in PPI at the 100-120 ms ISIs (*). An interesting
finding is that gating parameters in the AEP gating and PPI paradigms have
been found to be not correlated in rats (Ellenbroek et al 1999), which is in
agreement with findings of Schwarzkopf et al (1993) in humans.
Several pharmacological studies have found differential effects of drugs
on PPI and AEP gating. First, the DA D2/D3 agonist 7-OH-DPAT has been
found to disrupt PPI (Caine et al 1995; Varty and Higgens 1998; Ellenbroek et
al 1999), whereas no effect was found on AEP gating (Ellenbroek et al 1999).
36

Secondly, the PCP-induced reduction in AEP gating could be antagonized by
haloperidol (Adler et al 1986). However, haloperidol did not antagonize
effects of PCP on PPI (Geyer et al 1989; Keith et al 1991). Third, the 5-HT2receptor
agonist DOI decreased PPI and increased AEP gating in rats (Sipes
and Geyer 1994; Johnson et al 1998). Finally, apomorphine differentiated
between neonatal DA lesioned rats and sham lesioned rats in the PPI
paradigm (Schwarzkopf et al 1992), whereas no differentiation of the
apomorphine effect between both groups was found in the AEP gating
paradigm (Stevens et al 1996).
1.2.5. CONCLUSIONS
Given the above mentioned considerations it can be concluded that PPI and
AEP gating have neural substrates that show overlap on certain parts, but
also differ on other parts of the neural substrate.
Several questions remain to be answered
1.It is still not clear what the equivalent is for the human P50 in the
rat. Some (Miyazato et al 1996) propose an early component (the
P13), others suggest that the cortical N40-N50 is the equivalent
(Adler et al 1986). Considering these limitations, more research
should be focussed on comparing properties of the human P50 and
of rat midlatency AEP components. It is of particular importance to
investigate which of the above mentioned rat AEP components
respond in a similar fashion to certain experimental manipulations.
2.With respect to PPI, effects of the individual DA systems (ventral
and dorsal striatum) have been studied. However, also the role of
the DA balance between both DA systems could be an important
factor in the modulation of gating in the PPI and AEP gating
paradigms.
3.It has been shown that DA D2 receptors in the NAC play a
prominent role in PPI. It is not clear whether these NAC receptors
are involved in AEP gating as well. Systemic drug manipulations,
however, do not point in this direction, since amphetamine effects
on AEP gating were only partially antagonized by the D2 antagonist
sulpiride (Stevens et al 1991) and the D2 agonist 7-OH-DPAT did
not reduce AEP gating (Ellenbroek et al 1999). These discrepancies
should be studied further. Therefore, it is necessary to investigate
effects on AEP gating of drugs acting on D2 receptors in the NAC.
4.Systemic effects of non-competitive NMDA receptor antagonists
have reliably shown to decrease PPI. However, effects of such
drugs on AEP gating have only been studied twice and in the same
laboratory. A disruption of cortical AEP gating by PCP was found
and haloperidol restored this deficit (Adler et al 1986). Since PCP is
also known as a DA reuptake inhibitor, these effects could be
explained in terms of DA effects. Therefore, it is of interest to study
the influence of a more specific NMDA antagonistic drug in order to
compare effects of such a drug on PPI and AEP gating.
37

1.3. RAT GENOTYPES WITH DIFFERENT DA CHARACTERISTICS
1.3.1. APO-SUS AND APO-UNSUS
A non-invasive approach in studying the role of the DA system in gating is to
investigate information processing in rat genotypes that differ in distinct DA
systems. Two ratlines that show such clear differences are the apomorphine
unsusceptible (APO-UNSUS) and susceptible (APO-SUS) rats. These rat
genotypes have been obtained by pharmacogenetic selection.
"By means of pharmacogenetic selection, APO-SUS and
APO-UNSUS were developed. For a detailed description of the
original development of the APO-SUS and APO-UNSUS lines,
the reader is referred to Cools et al (1990). Briefly, all males
and females of a generation were submitted to the
apomorphine test and the mean gnawing score to the DA
agonist apomorphine (1.5 mg/kg, SC) per gender and litter was
determined. Out of the four highest male APO-SUS litters and
female APO-SUS litters the nine highest scoring males and
females were selected for the next APO-SUS generation.
Likewise, out of the four lowest male APO-UNSUS litters and
female APO-UNSUS litters, the nine lowest scoring males and
females were selected for the next APO-UNSUS generation.
Brother-sister pairings were prevented for each generation"
(Ellenbroek et al 2000).
The APO-SUS and APO-UNSUS show opposite characteristics concerning
certain aspects of their pharmacology, behavior and neuroendocrinological
and immunological systems (for review: Cools and Gingras 1998). Evidence
for differences between APO-SUS and APO-UNSUS in DA activity in various
brain areas was provided through assessment of pharmacological, behavioral
and biochemical measures (Cools et al 1990, 1997; Rots et al 1996;
Ellenbroek et al 2000).
First, APO-SUS rats display a high gnawing response following an
injection of an intermediate dose of apomorphine and therefore these rats are
characterized by a low DA activity in the dorsal striatum (caudate putamen,
CPu). In contrast, the APO-UNSUS display a low gnawing response to the
same dose of apomorphine and are characterized by a high DA activity in the
dorsal striatum (Cools et al 1990; Ellenbroek et al 2000). This has been
confirmed biochemically by Rots et al (1996). APO-SUS rats are characterized
by higher tyrosine hydroxylase (TH, the rate limiting enzyme in DA synthesis)
mRNA levels in the SNc and a higher density of D2/D3 binding sites and D1
receptor mRNA in the SNc projection area (predominantly the dorsal
striatum), suggesting an enhanced DA responsiveness for the nigrostriatal
system.
Secondly, based on the assessment of the locomotor activity on the
open-field following a challenge, the DA activity of the ventral striatum has
been established (see Cools et al 1990, 1991, and 1997). APO-SUS rats show
significantly more novelty-induced ambulatory behavior, habituate much
slower and are more susceptible to the behavioral effects of intermediate
doses of amphetamine than the APO-UNSUS. Therefore, it is thought that
APO-SUS rats have a higher DA reactivity of the mesolimbic system as
compared to the APO-UNSUS (Cools et al 1990).
38

Interestingly, Ellenbroek et al (1995) have found that APO-SUS rats
are characterized by diminished PPI as compared to rats of the APO-UNSUS
genotype. Other similarities with schizophrenia have also been described by
these authors: APO-SUS rats have elevated levels of mRNA for TH in the SNc
(Cools et al 1994); a heightened response to novelty (hyperarousal) (Cools et
al 1990); a reduced sensitivity for rheumatoid arthritis (Van der Langerijt et
al 1994) and a cognitive deficit in latent inhibition (Ellenbroek et al 1995). In
sum, it has been suggested that the APO-SUS may be an interesting model
for psychosis-prone patients.
Another difference between APO-SUS and APO-UNSUS is the incidence
of spike-wave-discharges (SWDs) in the EEG (Cools and Peeters 1991) (see
example of and SWD in Figure 1.14.). APO-SUS rats have more SWDs at the
age of six months as compared to the APO-UNSUS. Buzsáki et al (1990) have
proposed that the SWD incidence is related to differences in DA properties
between rat strains. For instance, Fisher 344 rats show more SWDs while
these rats also have a higher TH activity and D2 binding values in the SNc
and dorsal striatum as compared to Buffalo rats (Buzsáki et al 1990b).
Therefore, it has been suggested that the difference in SWDs between APO-
SUS and APO-UNSUS rats is also dependent on the DA properties in these
rats (Cools and Peeters 1992).
Figure 1.14.
SWD:
Example
1.3.2. WAG/RIJ AND ACI RATS
1 sec
Coenen, Van Luijtelaar and colleagues have been investigating one particular
rat genotype, the WAG/Rij rats, which show some resemblance with human
subjects with generalized absence epilepsy in EEG paroxysms and clinical
concomitants. The WAG/Rij rat is therefore considered as a genetic animal
model for absence epilepsy (for review Coenen et al 1992; Van Luijtelaar and
Coenen 1997). All adult WAG/Rij rats show spontaneous occurring SWDs with
a frequency of 7 to 9 Hz and a mean duration of 5 sec (Van Luijtelaar and
Coenen 1986). These SWDs have been found to occur predominantly during
intermediate levels of vigilance (Coenen et al 1990; Drinkenburg et al 1991).
ACI rats often serve as a control rat strain for the WAG/Rij rats, since these
rats appear to be virtually free of SWDs (Inoue et al 1990).
A genetic study (Peeters et al 1990a), in which the SWD incidence was
determined in F1 hybrids (WAG/Rij and ACI crossbreeding) indicated a
dominant inheritance of SWD occurrence. This is in agreement with findings
in human absence epilepsy (Metrakos and Metrakos 1970). In addition, based
on data on the inheritance of SWD number and duration, Peeters et al
(1990a) have concluded that the actual amount of SWDs is dependent on
more than one gene.
SWDs are thought to be due to synchronized responses of thalamocortical
neurons (TC). This synchronization process is considered to be caused
by the GABA-mediated output from the reticular thalamic nucleus (RTN)
(Steriade and Llinas 1988). Both the GABAergic and glutamatergic systems
39

have been implicated in SWDs. Pharmacological studies in WAG/Rij's have
shown that the GABA agonist muscimol increases, whereas the GABA
antagonist bicuculline decreases SWDs (Peeters et al 1989a). Furthermore,
the non-competitive NMDA antagonist MK-801 has been found to decrease
SWD number (Peeters et al 1989b). In contrast, NMDA has been found to
enhance epileptic activity (Peeters et al 1990b). However, as was also
described in the previous section, DA could play a role in SWDs as well. There
is an indication that DA might also play a modulatory role in the SWD
incidence in WAG/Rij rats, since the DA antagonist fluanisone has been shown
to induce a large increase in spike-wave activity in WAG/Rij's (Inoue et al
1994)
1.3.3. CONCLUSIONS
APO-SUS and APO-UNSUS rat genotypes have different DA properties and
also differ in information processing. APO-SUS rats show disturbances in PPI
and latent inhibition, which makes these rats a good model for schizophrenia.
It has been suggested that certain DA properties in particular rat
genotypes occur in parallel with spike-wave phenomena in the EEG. So, it can
be suggested that rats that differ in SWD incidence might also have different
DA properties. Therefore, WAG/Rij's and ACI that vary in SWD incidence,
could also posses different DA characteristics.
Several questions remain to be answered
1.AEP gating has not yet been studied in the APO-SUS and APO-
UNSUS rats. Therefore, the question is whether APO-SUS rats can
also be considered as a good model for AEP gating disturbances
seen in schizophrenic patients.
2.The question is whether other rat genotypes, besides the APO-
SUS and APO-UNSUS, also differ in DA properties. Given the
difference in SWD incidence in WAG/Rij’s and ACI rats and the
involvement of DA in SWDs, it is can be suggested that the
WAG/Rij and ACI strains might also differ in DA properties
3.When APO-SUS, APO-UNSUS, WAG/Rij and ACI rat differ in DA
balance between the ventral and dorsal striatum, it is of interest to
compare to compare these rats in the PPI and AEP gating
paradigms.
1.4. RATIONALE AND OBJECTIVES OF THE PRESENT STUDY
The goal of the present thesis is to analyze (1) to what extent the various DA
subsystems in the brain are involved in the information processing assessed
in the PPI and AEP gating paradigms and (2) to what extent these paradigms
represent similar or different aspects of information processing.
In humans, the P50 component has been shown to be dependent on
repetitive stimulation. Particularly, the amplitude to S1 has been found to
reduce with repeated stimulus presentation. Furthermore, it has been shown
human P50 gating decreases with longer interclick intervals (ISIs) due to an
increase in the response to S2. Since it is not immediately clear what the
equivalent is for the human P50 in the rat, it was determined which
40

midlatency cortical AEP components in the rat are also affected by repetitive
stimulation and the ISI in a similar fashion. Results of this experiment are
presented in chapter 2.
A relationship between the incidence of spike-wave discharges (SWDs)
and DA activity in circumscribed brain regions has been proposed. Therefore,
differences in SWD incidence could reflect differences in DA properties. This
holds true for the apomorphine susceptible (APO-SUS) and unsusceptible
(APO-UNSUS) rat genotypes. The DA properties of the APO-SUS rat genotype
have been suggested to contribute to the high incidence of SWDs. Indeed,
APO-UNSUS rats, characterized by opposite DA properties, show considerably
less SWDs than APO-SUS rats. To further test this hypothesis, effects on SWD
incidence of the DA antagonist haloperidol was tested in these two genotypes.
Also, the WAG/Rij (an animal model for absence epilepsy) and the nonepileptic
ACI strains were included in the experiment. Chapter 3 presents the
results of this study in which it was investigated whether the four types of
animals form a continuum with respect to the incidence of SWDs at baseline
and following haloperidol, and probably with respect to the DA activity as
well.
In order to firmly conclude that indeed the four rat genotypes differ in
their DA properties, the activity of the DA system in various brain structures
was established through assessment of behavioral responses. In chapter 4,
we therefore present the study on these behavioral responses in the four rat
genotypes. First, the DA activity in the dorsal striatum (caudate-putamen,
CPu) was measured in a stereotypy paradigm. Secondly, novelty induced
spontaneous activity and amphetamine induced locomotor stimulation was
measured on an open-field to determine the DA reactivity in the ventral
striatum (nucleus accumbens, NAC).
Since the DA system has been shown to play a prominent role in PPI
and also is involved in AEP gating, the next step was to study whether the
four rat genotypes that differ in their DA properties would also show
differences in the two information processing paradigms. In chapter 5, the
results of this study are presented.
It has been suggested that DA D2 receptors in the mesolimbic DA
terminal region in the NAC regulate PPI. For AEP gating this involvement is by
no means clear. Chapter 6 deals with this question. Here, the effects of NAC
microinjections of the DA D2/D3 agonist quinpirole on both cortical and
hippocampal AEP gating are presented. Furthermore, the results on the
possible antagonistic effect of the DA D2 antagonist haloperidol are shown.
Considering that two subregions of the NAC, the shell and the core, have
been found to differ anatomically as well as functionally, it was decided to
separately analyze the effects of quinpirole on AEP gating in both these NAC
sites.
Besides the effects of the DA system on both PPI and AEP gating, also
a reduction in glutamatergic activity in the brain has been shown to be an
important factor in gating mechanisms. In chapter 7, therefore, we present
the study on the effects of the non-competitive NMDA receptor antagonist
ketamine on both types of gating. The main aim of this study was to
determine whether the glutamatergic system is differentially involved in AEP
gating and PPI.
Finally, chapter 8 gives an overview of the results and the subsequent
discussion.
41

1.5. REFERENCES
Abduljawad KA, Langley RW, Bradshaw CM, Szabadi E (1997) Effects of clonidine and diazepam on the
acoustic startle response and on its inhibition by 'prepulses' in man. J Psychopharmacology 11:29-
34
Abduljawad KA, Langley RW, Bradshaw CM, Szabadi E (1999) Effects of bromocriptine and haloperidol
on prepulse inhibition: comparison of the acoustic startle eyeblink response and the N1/P2 auditoryevoked
response in man. J Psychopharmacology 13:3-9
Adler LE, Pachtman E, Franks RD, Pecevich, Waldo MC, Freedman R (1982) Neurophysiological
evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol
Psychiatry 17:639-653
Adler LE, Waldo MC, Freeman R (1985) Neurophysiologic studies of sensory gating in schizophrenia:
comparison of auditory and visual responses. Biol Psychiatry 20:1284-1296
Adler LE, Rose G, Freedman R (1986) Neurophysiological studies of sensory gating in rats: effects of
amphetamine, phencyclidine, and haloperidol. Biol Psychiatry 21: 787–798
Adler LE, Pang K, Gerhardt G, Rose GM (1988) Modulation of the gating of auditory evoked potentials
by norepinephrine: pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry
24:179-190
Adler LE, Waldo MC, Tatcher A, Cawthra E, Baker N, Freedman R (1990) Lack of relationship of
auditory gating defects to negative symptoms in schizophrenia. Schizophrenia Res 3:131-138
Adler LE, Waldo MC. (1991) Counterpoint: Sensory Gating-Hippocampal Model of Schizophrenia.
Schizophr Bull 17:19-24.
Adler LE, Hope C, Hoffner LD, Stephen C, Young D, Herhardt G (1994) Bromocriptine impairs P50
auditory sensory gating in normal control subjects. Biol Psychiatry 35:630
Adler LE, Olincy A, Waldo M, Harris JG, Griffith JG, Stevens K, Flach K, Nagamoto H, Bickford P,
Leonard S, Freedman R (1998) Schizophrenia, sensory gating and nicotine receptors. Schizophr Bull
24:189-202.
Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate
mechanisms. Brain Res Brain Res Rev 31: 302-312
Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends
Neurosci 12: 366–375
Aldes LD (1988) Thalamic connectivity of rat somatic motor cortex. Brain Res Bull 20:333-348
Alexander GE, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates
of parallel processing. Trends Neurosci 13: 266-271
Andersen RA, Knight PL, Merzenich MM (1980) The thalamocortical and corticothalamic connections of
AI, AII, and the anterior auditory field (AAF) in the cat: evidence for two largely segregated systems
of connections. J Comp Neurology 194:663-701.
Amalric M, Koob GF (1993) Functionally selective neurochemical afferents and efferents of the
mesocorticolimbic and nigrostriatal dopamine system. Prog Brain Res 99:209-226
Amalric M, Koob GF (1987) Depletion of dopamine in the caudate nucleus but not in nucleus
accumbens impairs reaction-time performance in rats. J Neurosc 7:2129-2134
Amaral DG, Witter MP (1995) Chapter 21: Hippocampal formation. In: The rat nervous system,
Paxinos G (Eds) Academic Press, London, UK, pp 443-493
Arts MP, Cools AR (1998) Bilateral 6-hydroxydopamine lesion in the dopaminergic A8 cell group
produces long-lasting deficits in motor programming of cats. Behav Neurosci 112:102-115.
Baker N, Adler L, Franks RD, Waldo M, Berry S, Nagamoto H, et al. (1987) Neurophysiological
assessment of sensory gating in psychiatric inpatients: Comparison between schizophrenia and
other diagnoses. Biol Psychiatry 22:603-617
Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption of prepulse inhibition
produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394-8401.
Bakshi VP, Swerdlow NR, Braff DL, Geyer MA (1998) Reversal of isolation rearing-induced deficits in
PPI by Seroquel and olanzapine. Biol Psychiatry 43:436-445
Bakshi VP, Geyer MA (1999) Ontogeny of isolation rearing-induced deficits in sensorimotor gating in
rats. Physiol Behav 67:385-392
Bassareo V, Di Chiara G (1999) Differential responsiveness of dopamine transmission to food stimuli
in nucleus accumbens shell/core compartments. Neuroscience 89:637-641
Bardgett ME, Olney JW, Jackson JL, Wrona CT, Csernansky JG (1993) Connecting hippocampal
neuropathy with dopamine dysfunction in schizophrenia: IVC kainic acid as an animal model. Soc
Neurosc Abstr 19:8
Bardgett ME, Jackson JL, Taylor GT, Csernasky JG (1995) Kainic acid decreases hippocampal neuronal
number and increase in dopamine receptor binding in the nucleus accumbens: an animal model of
schizophrenia. Behav Brain Res 70:153-164
Barkley RA (1998) Attention-deficit hyperactivity disorder. Sci Am 279: 66-71
Berendse HW, Groenewegen HJ (1991) Restricted cortical termination fields of the midline and
intralaminar thalamic nuclei in the rat. Neuroscience 42:73-102
Berendse HM, Galis-de-Graaf Y, Groenewegen HJ (1992) Topographic organization and relationship
with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol
316:314-347
Berger B, Thierry AM, Tassin JP, Moyne MA (1976) Dopaminergic innervation of the rat prefrontal
cortex: a fluorescence histochemical study. Brain Res 106:133-145
42

Bernstein SN, Beninger RJ (2000) Turning in rats following intraaccumbens shell injections of
amphetamine or eticlopride. Pharmacol Biochem Behav 65:203-207
Bickford-Wimer PC, Nagamoto H, Johnson R, Adler LE, Egan M, Rose GM, Freedman R (1990) Auditory
sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:174-182
Bickford-Wimer P, Nagamoto H, Johnson R, Adler L, Egan M, Rose GM, Freedman R (1990) Sensory
gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:183–192
Bickford PC, Luntz-Leybman V, Freedman R (1993) Auditory sensory gating in the rat HPC: Modulation
by brainstem activity. Brain Res 607:33-38
Björklund A, Lindvall O (1984) Dopamine-containing system in the CNS. In: Björklund A, Hökfelt O
(Eds) Classical transmitters in the CNS, Part I (Handbook of chemical neuroanatomy). Elsevier,
Amsterdam, pp 55-122
Blumenthal TD, Gescheider GA (1987) Modification of the acoustic startle reflex by a tactile prepulse:
the effects of stimulus onset asynchrony and prepulse intensity. Psychophysiology 24:320-327
Blumenthal TD, Flaten MA (1994) Selective effects of attentional direction on the startle reflex at
different stages of processing. Psychobiology 22:338-346
Blumenthal TD (1995) PPI of the startle eyeblink as an indicator of temporal summation.
Percept Psychophys 57:487-494.
Bolam JP, Izzo IN, Graybiel AM (1988) Cellular substrate of the histochemically defined
striosome/matrix system of the caudate nucleus: A combined Golgi and immunocytochemical study
in cat and ferret. Neuroscience 24:853–875
Bourdelais A, Kalivas PW (1990) Amphetamine lowers extracellular GABA concentration in the ventral
pallidum. Brain Res 516:132-136
Boutros NN, Torello MW, Barker BA, Tueting PA, Wu SC, Nasrallah HA (1995). The P50 evoked
potential component and mismatch detection in normal volunteers: implications for the study of
sensory gating. Psychiatry Res 57:83-88
Boutros NN, Bonnet KA, Millana R, Liu J (1997) A parametric study of the N40 auditory evoked
potential. Biol Psychiatry 42:1051-1059
Boutros NN, Belger A (1999) Midlatency evoked potentials attenuation and augmentation reflect
different aspects of sensory gating. Biol Psychiatry 45:917-922
Boutros NN, Belger A, Campbell D, D'Souza CD, Krystal J (1999) Comparison of four components of
sensory gating in schizophrenia and normal subjects: a preliminary report. Psychiatry Res 88:199-
130
Bouyer JJ, Park DH, Joh TH, Pickel VM (1984) Chemical and structural analysis of the relation between
cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum. Brain Res
302:267–275
Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Prestimulus effects on human startle
reflex in normals and schizophrenics. Psychophysiology 14: 339–343
Braff DL, Grillon C, Geyer MA (1992a) Sensorimotor gating and schizophrenia: human and animal
model studies. Arch Gen Psychiatry 47:181–188
Braff DL, Grillon C, Geyer MA (1992b) Gating and habituation of the startle reflex in schizophrenic
patients. Arch Gen Psychiatry 49:206-215
Braff DL (1993) Information processing and attention dysfunctions in schizophrenia. Schizophr Bull
18:233–259
Braff DL, Swerdlow NR, Geyer MA (1999) Symptom correlates of prepulse inhibition deficits in male
schizophrenic patients. Am J Psychiatry 156:596-602
Breier A (1995) Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 14:187-202
Bristow LJ, Landon L, Saywell KL, Tricklebank MD (1995) The glycine/NMDA receptor antagonist, L-
701,324 reverses isolation-induced deficits in PPI in the rat. Psychopharmacology 118:230-232
Bubser M, Koch M (1994) Prepulse inhibition of the acoustic startle response of rats is reduced by 6hydroxydopamine
lesions of the medial PFC. Psychopharmacology 113:487-492
Buzsaki G, Laszlovszky I, Lajtha A, Vadasz C (1990) Spike-and-wave neocortical patterns in rats:
genetic and aminergic control. Neuroscience 38:323-333
Cacace AT, Satya-Murti S, Wolpaw JR (1990) Human middle-latency auditory evoked potentials:
vertex and temporal components. Electroenceph Clin Neurophysiol 77:6-18
Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle prepulse inhibition and habituation in
patients with schizotypal personality disorder. Am J Psychiatry 150:1862-1867.
Cadenhead KS, Swerdlow NR, Shafer K, Diaz M, Braff DL (1999) Modulation of the startle response
and laterality in schizophrenic patients, their relatives and schizotypical personality disorder:
evidence of inhibitory deficits. Proc Am Acad Neuropsychopharmacology 136
Cadenhead KS, Light GA, Geyer MA, Braff DL (2000) Sensory gating deficits assessed by the P50
event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry 157:55-59
Caine SB, Geyer MA, Swerdlow NS (1992) Hippocampal modulation of acoustic startle response and
prepulse inhibition in the rat. Pharmacol Biochem Behav 43: 1201–1208
Caine SB, Geyer MA, Swerdlow NR (1995) Effects of D3/D2 dopamine receptor agonists and
antagonists on PPI of acoustic startle in the rat. Neuropsychopharmacology 12:139-145
Calloway E (1973) Habituation of averaged evoked potentials in man. In: HVS Peeke, MJ Herz (Eds).
Habituation. New York: Academic Press, pp 153-174
Campeau S, Davis M (1995) Prepulse inhibition of the acoustic startle reflex using visual and auditory
prepulses: disruption by apomorphine. Psychopharmacology 117:267-274
Cardenas VA, McCallin K, Hopkin R, Fein G (1997) A comparison of the repetitive and conditioningtesting
P50 paradigm. Electroenceph Clin Neurophysiol 104:157-164
43

Carlsson A (1988) The current status of the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology 1:197
Carlsson M, Carlsson A (1990) Interactions between glutamatergic and monoaminergic systems within
the basal ganglia: Implications for schizophrenia and Parkinson's disease. Trends Neurosci 13: 272-
276
Carpenter MB (1978) Core text of neuroanatomy. Williams and Wilkins, Baltimore
Carter CJ, Pycock CJ (1980) Behavioral and biochemical effects of dopamine and noradrenaline
depletion within the medial prefrontal cortex of the rat. Brain Res 192:163-76
Castellanos FX, Fine EJ, Hallett M (1996) Sensorimotor gating in boys with Tourette’s syndrome and
ADHD: preliminary results. Biol Psychiatry 39:33-41
Chevalier G, Vacher S, Deniau JM, Desban M (1985) Disinhibition as a basic process in the expression
of striatal function I: The striatonigral influence on tecto-spinal/tecto-diencephalic neurons. Brain
Res 334:215–226
Chiappa KH (1983) Evoked potentials in clinical medicine. Raven Press, New York
Civelli et al (1993) Molecular diversity of the dopamine receptors. Ann Rev Pharmacol Toxicol 32:281
Clementz AR, Geyer MA, Braff DL (1997) P50 suppression among schizophrenia and normal
comparison subjects: a methodological analysis. Biol Psychiatry 41: 1035–1044
Coenen AML, Drinkenburg WHIM, Peeters BWMM, Vossen JMH, Van Luijtelaar ELJM (1990) Absence
epilepsy and the level of vigilance in rats of the WAG/Rij strain. Neurosc Biobehav Rev 15:259-263
Coenen AM, Drinkenburg WH, Inoue M, Luijtelaar EL (1992) Genetic models of absence epilepsy, with
emphasis on the WAG/Rij strain of rats. Epilepsy Res 12:75-86
Cools AR, Van Rossum (1976) Excitation-mediated and inhibition-mediated dopamine receptors: a
new concept towards a better understanding of electrophysiological, biochemical, pharmacological,
functional and clinical data. Psychopharmacologia 45:243-254
Cools AR, Struyker Boudier HAJ, Van Rossum JM (1976) Dopamine receptors: selective agonists and
antagonists of functionally distinct types within the feline brain. Eur J Pharmacol 37:283-293
Cools AR (1977) Two functionally and pharmacologically distinct receptors in the rat brain. In Costa E,
Gessa GL (Eds) Advances in biochemical psychopharmacology. New York: Raven Press, pp 215-225
Cools AR, Jaspers R, Schwarz M, Sontag KH, Vrijmoed De Vries M, Van den Bercken J (1984) Basal
ganglia and switching motor programs. In: McKenzie JS, Klemm RE, Wilcock LN (Eds). Basal
ganglia: structure and function. New York: Plenum Press, pp 513-544
Cools AR, Brachten R, Heeren D, Willemen A, Ellenbroek B (1990) Search after neurobiological profile
of individual-specific features of Wistar rats. Brain Res Bull 24:49-69
Cools AR, Van de Bos R, Ploeger G, Ellenbroek BA (1991) Gating function of noradrenaline in the
ventral striatum: its role in behavioral responses to environmental and pharmacological challenges.
In: Willner P, Scheel-Kruger J (Eds). The mesolimbic DA system: from motivation to action, pp 141-
173
Cools AR, Peeters BW (1992) Differences in spike-wave discharges in two rat selection lines
characterized by opposite dopaminergic activities. Neurosci Lett 134:253-256
Cools AR, de Beltran KK, Prinssen EPM, Koshikawa N (1993) Differential role of core and shell of the
nucleus accumbens in jaw movements of rats. Neurosc Res Comm 14:55-61
Cools AR, Miwa Y, Koshikawa N (1995) Role of dopamine D1 and D2 receptors in the nucleus
accumbens in jaw movements of rats: a critical role of the shell. Eur J Pharmacology 286:41-47
Cools AR, Ellenbroek BA, Gingras MA, Engbersen A, Heeren D (1997). Differences in vulnerability and
susceptibility to dexamphetamine in Nijmegen high and low responders to novelty: a dose-effect
analysis of spatio-temporal programming of behaviour. Psychopharmacology 132:181–187
Cools AR, Gingras MA (1998) Nijmegen high and low responders to novelty: a new tool in the search
after the neurobiology of drug abuse liability. Pharmacol Biochem Behav 60:151-159
Cooper JR, Bloom FE, Roth RH (1991) The Biochemical Basis of Neuropharmacology (6th ed.). New
York: Oxford University Press.
Cullum CM, Harris JG, Waldo MC, Smernoff E, Madison A, Nagamoto HT, Griffith J, Adler LE, Freedman
R (1993) Neurophysiological and neuropsychological evidence for attentional dysfunction in
schizophrenia. Schizophr Res 10:131-141
Davis M, Gendelman D, Tischler M, Geldelman P (1982) A primary acoustic startle circuit: Lesion and
stimulation studies. J Neurosc 2:791-805.
Decker MW, Curzon P, Brioni JD (1995) Influence of separate and combined septal and amygdala
lesions on memory, acoustic startle, anxiety, and locomotor activity in rats. Neurobiol learning
Memory 64:156-168
Deniau JM, Chevalier G (1985) Disinhibition as a basic process in the expression of striatal functions
II: The striato-nigral influence on thalamocortical cells of the ventromedial thalamic nucleus. Brain
Res 334:227–233
Descarries TW, Lemay B, Doucet G, Berger B (1987) Regional and laminar density of the dopamine
innervation in adult rat cerebral cortex. Neuroscience 21:807-824
Di Chiara G, Imperato A (1988a) Drugs abused by humans preferentially increase synaptic dopamine
concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci 85:5274-5278
Donoghue JP, Herkenham M (1986) Neostriatal projections from individual cortical fields conform to
histochemically distinct striatal compartments in the rat. Brain Res 365:397–403
Drinkenburg WHIM, Coenen AML, Vossen JMH, Van Luijtelaar (1991) Spike-wave discharges and
sleep-wake states in rats with absence epilepsy. Epilepsy Res 9:218-224
Duffy FH, Iyer VG, Surwillo WW (1989) Clinical Electroencephalography and Topographic Brain
Mapping: Technology and Practice. Springer-Verlag New York Inc, New York
44

Eccles JC (1969) The Inhibitory Pathways of the Central Nervous System. Charles C Thomas Publisher,
Springfield
Ellenbroek BA, Cools AR (1990) Animal models with construct validity for schizophrenia. Behav
Pharmacol 1: 469–490
Ellenbroek BA, Cools AR (1995a) Animal models of psychotic disturbances. In: den Boer JA,
Westenberg HGM, van Praag HM (Eds) Advances in the neurobiology of schizophrenia. Wiley,
Chichester, pp 89–109
Ellenbroek BA, Cools AR (1995b) Towards an integration of animal models and clinical concepts of
schizophrenia. Acta Neuropsychiatry 7:S64–S67
Ellenbroek BA, Geyer MA, Cools AR (1995) The behavior of APO-SUS rats in animal models with
construct validity for schizophrenia. J Neurosci 15:7604–7611
Ellenbroek BA, Budde S, Cools AR (1996) Prepulse inhibition and latent inhibition: the role of
dopamine in the medial prefrontal cortex. Neuroscience 75:535–542
Ellenbroek BA, van den Kroonenberg PT, Cools AR (1998a) The effects of an early stressful life event
on sensorimotor gating in adult rats. Schizophr Res 30:251-260
Ellenbroek BA, van Luijtelaar G, Frenken M, Cools AR (1999) Sensory gating in rats: lack of correlation
between auditory evoked potential gating and PPI. Schizophr Bull 25:777-788
Ellenbroek BA, Sluyter F, Cools AR (2000) The role of genetic and early environmental factors in
determining apomorphine susceptibility. Psychopharmacology 148:124-131
Ettenberg A (1989) Dopamine, neuroleptics and reinforced behavior. Neurosci Biobehav Rev 13:105-
111
Fallon JH, Loughlin SE MP (1995) Chapter 12: Substantia nigra. In: The rat nervous system, Paxinos G
(Eds) Academic Press, London, UK, pp 215-237.
Fendt M, Koch M (1999) Cholinergic modulation of the acoustic startle response in the caudal pontine
reticular nucleus of the rat. Eur J Pharmacol 370:101-107
Ferino F, Thierry AM, Saffroy M, Glowinski J (1987) Interhemispheric and subcortical collaterals of
medial prefrontal cortical neurons in the rat. Brain Res 417:257–266
Filion D, Dawson ME, Schell AM (1993) Modification of the acoustic startle-reflex eyeblink: a tool for
investigating early and late attentional processes. Biol Psychology 35:185-200
Filion D, Dawson ME, Schell AM (1998) The psychological significance of human startle eyeblink
modification: a review. Biol Psychology 47:1-43
Flach KA, Gerhardt KA, Adler LE (1995) Interactions between the cholinergic and dopaminergic
systems in a computer-model of sensory gating in the CA3 neural-network of the hippocampus.
Schizophr Res 15: 173-173
Franks RD, Adler LE, Waldo MC, Alpert J, Freedman R (1983) Neurophysiological studies of sensory
gating in mania: comparison with schizophrenia. Biol Psychiatry 18:989-1005
Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD (1983) Neurophysiological evidence for a
defect in inhibitory pathways in schizophrenia: Comparison of medicated and drug-free patients.
Biol Psychiatry 18:537-551
Freedman R, Mirsky AF (1991) Event related potentials: exogenous components. In: Steinhauer SR,
Gruzelier JH, Zubin J (Eds) Handbook of schizophrenia, vol 5: neuropsychology, psychophysiology
and information processing. Elsevier, Amsterdam, pp 71–90
Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased
numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22-33
Freedman R, Adler LE, Myles-Worsley M, Nagamoto HT, Miller C, Kisley M, McRae K, Waldo M (1996)
Inhibitory gating of an evoked response to repeated auditory stimuli in schizophrenic and normal
subjects: human recordings, computer simulation, and an animal model. Arch Gen Psychiatry
53:1114-1121
Freund TF, Powell JF, Smith AD (1984) Tyrosine hydroxylase-immunoreactive boutons in synaptic
contact with identified striatonigral neurons with particular reference to dendritic spines.
Neuroscience 13:1189–1215
Fuxe K, Agnati LF, Kalia M, Goldstein M, Andersson K, Härfstrand A (1985) Dopaminergic system in
the brain and pituitary. In: Fluckiger E, Muller EE, Thorner MO (Eds) The dopaminergic system
(Basic and clinical aspects of neuroscience). Springer-Verlag, Berlin, pp 11-25
Gelissen M, Cools AR (1988) Effect of intracaudate haloperidol and apomorphine on switching motor
patterns upon current behavior of cats. Brain Res 29:17-26
Gerfen CR (1984) The neostriatal mosaic: Compartmentalization of corticostriatal input and
striatonigral output systems. Nature 311:461–464
Gerfen CR (1985) The neostriatal mosaic: I Compartmental organization of projections from the
striatum to the substantia nigra in the rat. J Comp Neurol 236:454–476
Gerfen CR, Herkenham M, Thibault J (1987a) The neostriatal mosaic: II Patch– and matrix-directed
mesostriatal dopaminergic and non-dopaminergic systems. J Neurosci 7:3915–3934
Gerfen CR, Herkenham M, Thibault J (1987b) The neostriatal mosaic: III Biochemical and
developmental dissociation of patch-matrix mesostriatal systems. J Neurosci 7: 3935-3944
Gerfen CR (1989) The neostriatal mosaic: Striatal patch-matrix organization is related to cortical
lamination. Science 246:385–388
Gerfen CR, Baimbridge KG, Miller JJ (1985) The neostriatal mosaic: Compartmental distribution of
calcium binding protein and parvalbumin in the basal ganglia of the rat and monkey. Proc Natl Acad
Sci USA 82: 8780–8784.
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, et al (1990) D1 and D2 dopamine receptorregulated
gene expression of striatonigral and striatopallidal neurons. Science 250:1429–1432
45

Gerfen CR (1992a) The neostriatal mosaic: multiple levels of compartmental organization. Trends
Neurosci 15:133-139
Gerfen CR (1992b) The neostriatal Mosaic: multiple Levels of compartmental organization in the basal
ganglia. Ann Rev Neurosci 15:285–320
Gewirtz JC, Davis M (1995) Habituation of prepulse inhibition of the startle reflex using an auditory
prepulse close to background noise. Behav Neurosc 109:388-395
Geyer MA, Braff DL, Mansbach RS (1989) Failure of haloperidol to block the disruption of sensory
motor gating induced by phencyclidine and MK801. Biol Psychiatry 25: 169A–170A
Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990) Startle response models of sensorimotor
gating and habituation deficits in schizophrenia. Brain Res Bull 25: 485–498
Goeders NE, Smith JE (1983) Cortical dopaminergic involvement in cocaine reinforcement. Science
221: 773-5
Gottesman II (1991) Schizophrenia genesis. EH Freeman, New York
Graham FK, Murray GM (1977) Discordant effects of weak prestimulation on magnitude and latency of
the blink reflex. Physiol Psychol 5:108-114
Griffith JM, Waldo M, Adler LE, Freedman R (1993) Normalization of auditory sensory gating in
schizophrenics after a brief period for sleep. Psychiatric Res 49:29-39
Griffith JM, Freedman R (1995) Normalization of the auditory P50 gating deficit of schizophrenic
patients after NREM, but not REM sleep. Psychiatry Res 56:271- 278
Griffith JM, O'Neill JE, Petty F, Garver DL (1996) Effects of nicotine and stage 2 sleep on auditory P50
gating in schizophrenia. [Abstract] Biol Psychiatry 39:652
Groenewegen HJ, Vermeulen-Van de Zee E, Te Kortschot A, Witter (1987) Organization of the
projections from the subiculum to the ventral striatum in the rat. A study using anterograde
transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 23:103-120
Groenewegen HJ, Berendse HW, Haber SN (1993) Organization of the output of the ventral pallidal
system in the rat: ventral pallidal efferents. Neuroscience 57:113-142
Groenewegen HJ, Berendse HW (1994) The specificity of the non-specific midline and intralaminar
thalamic nuclei. Trends Neurosc 17:52-57
Groenewegen HJ, Wright CI, Beijer AVJ (1996) The nucleus accumbens: gateway for limbic structures
to reach the motor system? In: The emotional motor system, G Holstege, R Bandler, CB Saper
(Eds) Prog Brain Res 107:485-511
Groenewegen HJ, Galis de Graaf Y, Smeets WJ (1999a) Integration and segregation of limbic corticostriatal
loops at the thalamic level: an experimental tracing study in rats. J Chem Neuroanatomy
16: 167-185
Groenewegen HJ, Wright CI, Beijer AV, Voorn P (1999b) Convergence and segregation of ventral
striatal inputs and outputs. Ann NY Acad Sci 877: 49-63
Guberman A, Bruni J (1999) Essentials of clinical epilepsy. Boston: Butterworth Heinemann
Halgren E, Stapleton J, Smith M, Altafullah I (1986) Generators of the human scalp P3s. In: Cracco
RQ, Bodis-Wollner I (Eds). Evoked Potentials. New York: Alan R Liss, pp 269-284
Harrison J B, Woolf N J, Buchwald J S (1990) Cholinergic neurons in the feline pontomesencephalon. I.
Essential role in 'Wave A' generation. Brain Res 520:43-54
Hattori T, McGeer EG, McGeer PL (1978) Fine structural analysis of corticostriatal pathway. J Comp
Neurol 185: 347–354
Heimer L. Alheid G (1991) Piecing together the puzzle of basal forebrain anatomy. In: TC Napier, P
Kalivas, I Hanin (Eds) The basal forebrain: anatomy to function. Plenum Press, NY, p 1-42
Heimer L, Zahm DS, Alheid GF (1995) Basal ganglia. In: Paxinos G (Eds) The rat nervous system.
Academic Press, San Diego, New York, Boston, London, Sydney, Tokyo, Toronto
Hershman KM, Freedman R, Bickford PC (1995) GABA-B antagonists diminish the inhibitory gating of
auditory response in the rat hippocampus. Neuroscience Letters, 190:133-136
Hoffman HS, Searle JL (1968) Acoustic and temporal factors in the avocation of startle. J Acoust Soc
Am 43:269-282
Hoffman HS, Ison JR (1980) Reflex modification in the domain of startle: I. some empirical findings
and their implications for how the nervous system processes sensory input. Psychol Rev 87:175-189
Hoffman DC, Donovan H (1994) D1 and D2 dopamine receptor antagonists reverse PPI deficits in an
animal model of schizophrenia. Psychopharmacology 115:447-453
Hutchison KE, Swift R (1999) Effect of d-amphetamine on PPI of the startle reflex in humans.
Psychopharmacology 143:394-400
Ishizuka N, Weber J, Amaral DG (1990) Organization of intrahippocampal projections originating from
CA3 pyramidal cells in the rat. J Comp Neurol 295:580-623
Imig TJ, Morel A (1988) Organization of the Cat's Auditory Thalamus. In: Auditory Function:
Neurological Bases of Hearing. GM Edelman, WE Gall, WM Cowan (Eds), The Neurosciences Institute
(John Wiley & Sons), New York, pp 457-484
Inglis WL, Dunbar JS, Winn P (1994) Outflow from the nucleus accumbens to the pedunculopontine
tegmental nucleus: a dissociation between locomotor activity and the acquisition of responding for
conditioned reinforcement stimulated by d-amphetamine. Neuroscience 62:51-64
Inoue M, Peeters B, Van Luijtelaar E, Vossen J, Coenen A (1990) Spontaneous occurrence of spikewave
discharges in five inbred strains of rats. Physiol Behav 48:199-201
Inoue M, Ates N, Vossen JMH, Coenen AML (1994) Effects of the neuroleptanalgesic Fentanyl-
Fluanisone (Hypnorm) on spike-wave discharges in epileptic rats. Pharmacol Biochem Behav 48:
547-551
46

Irvine DRF, Jackson GD (1983). Auditory input to neurons in mesencephalic and rostral pontine
reticular formation: An electrophysiological and horseradish peroxidase study in the cat. J
Neurophys 49:1319-1333
Ison JR, Hammond GR, Krauer EE (1973) Effects of experience on stimulus-produced reflex-inhibition
in the rat. Physiol behav 83:324-336
Ison JR, Ashkinazi B (1980) Effects of a warning stimulus on reflex elicitation and reflex inhibition.
Psychophysiology 17:586-591
Ison JR, Sanes JN, Foss JA, Pinckney LA (1990) Facilitation and inhibition of the human startle blink
reflexes by stimulus anticipation. Behav Neurosci 104:418–429
Jaber M, Robinson SW, Missale C, Caron MG (1996) Dopamine receptors and brain function.
Neuropharmacology 35:1503-19
Jackson DM, Anden NE, Dahlstrom A (1975a) A functional effect of dopamine in the nucleus
accumbens and in some other dopamine-rich parts of the rat brain. Psychopharmacologia 45:139-
49
Jackson DM, Anden NE, Engel J, Liljequist S (1975b) The effect of long-term penfluridol treatment on
the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striatum.
Psychopharmacologia 45:151-155
Jackson DM, Westlund-Danielsson A (1994) Dopamine receptors: molecular biology biochemistry and
behavioral aspects. Pharmacol Ther 64:291-369
Jarvie and Caron (1993) Heterogeneity of dopamine receptors. Adv Neurol 60:325
Japha K, Koch M (1999) Picrotoxin in the medial prefrontal cortex impairs sensorimotor gating in rats:
reversal by haloperidol. Psychopharmacology 144:347-354
Jaspers R, Swarz M, Sontag KH, Cools AR (1984) Caudate nucleus and programming behavior in cats:
role of dopamine in switching motor patterns. Behav Brain Res 14:17-28
Jaspers RM, De Vries TJ, Cools AR (1990) Effects of intrastriatal apomorphine on changes in switching
behavior induced by the glutamate agonist AMPA injected into the cat caudate nucleus. Behav Brain
Res 37:247-254
Jennings PD, Schell AM, Filion D, Dawson ME (1996) Tracking early and late stages of information
processing: contributions of startle eyeblink reflex modification. Psychophysiology 33:148-155
Jimenez-Castellanos J, Graybiel AM (1987) Subdivisions of the dopamine-containing A8-A9-A10
complex identified by their differential mesostriatal innervation of striosomes and extrastriosomal
matrix. Neuroscience 23: 223–242
Jimenez-Castellanos J, Graybiel AM (1989) Compartmental origins of striatal efferent projections in
the cat. Neuroscience 32: 297–321
Jin Y, Potkin SG, Patterson JV, Sandman CA, Hetrick WP, Bunney WE Jr (1997) Effects of P50
temporal variability on sensory gating in schizophrenia. Psychiatry Res 70:71-81
Jin Y, Bunney WE Jr, Sandman CA, Patterson JV, Fleming K, Moenter JR, Kalali AH, Hetrick WP, Potkin
SG (1998) Is P50 suppression a measure of sensory gating in schizophrenia? Biol Psychiatry
43:873-878
Johansson C, Jackson DM, Svensson L (1994) The atypical antipsychotic, remoxipride, blocks
phencyclidine-induced disruption of prepulse inhibition in the rat. Psychopharmacology 116:37–442
Johansson C, Jackson DM, Zhang J, Svensson L (1995) Prepulse inhibition of acoustic startle, a
measure of sensorimotor gating: effects of antipsychotics and other agents in rats. Pharmacol
Biochem Behav 52:649–654
Johnson RG, Stevens KE, Rose GM (1998) 5-Hydroxytryptamine2 receptors modulate auditory filtering
in the rat. J Pharmacol Exp Ther 285:643-650
Jones E G (1985) The Thalamus. Plenum Press, New York
Jones CK, Shannon HE (2000) Effects of scopolamine in comparison with apomorphine and
phencyclidine on prepulse inhibition in rats. Eur J Pharmacol 391:105-112
Jongen-Relo AL, Groenewegen HJ, Voorn O (1993) Evidence for a compartmental histochemical
organization of the nucleus accumbens in the rat. J Comp Neurol 337:267-276
Judd LL, McAdams L, Budnick B, Braff DL (1992) Sensory gating deficits in schizophrenia: New results.
Am J Psychiatry 149:488-493
Kalat JW (1995) Biological Psychology, 5 th edition, pp 564-579
Karson CN, Garcia-Rill E, Biedermann J, Mrak RE, Husain MM, Skinner RD (1991) The brainstem
reticular formation in schizophrenia. Psychiatry Res 40:31-48
Karper LP, Freeman GK, Grillon C, Morgan CA, Charney DS, Krystal JH (1996) Preliminary evidence of
an association between sensorimotor gating and distractibility in psychosis. J Neuropsychiatry Clin
Neurosc 8:60-66
Kawaguchi Y, Wilson CJ, Emson P (1990) Projection subtypes of rat neostriatal matrix cells revealed
by intracellular injection of biocytin. J Neurosci 10:3421–3438
Keith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine
and dizocilpine on prepulse inhibition of startle. Biol Psychiatry 30:557–566
Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat
following 6-OHDA lesions of the accumbens septi and corpus striatum. Brain Res 94:507-522
Kelly JP (1991) Chapter 32: Hearing In: Kandel ER, Schwarz JH, Jessell TM (Eds) Principles of neural
science. Prentice Hall International, London, UK, pp 481-499
Kita H, Chang HT, Kitai ST (1983) Pallidal inputs to subthalamus: Intracellular analysis. Brain Res
264:255–265
Kita H, Kitai ST (1987a) Efferent projections of the subthalamic nucleus in the rat: Light and electron
microscopic analysis with the PHA-L method. J Comp Neurol 260:435–452
47

Kita H, Kitai ST (1987b) Subthalamic inputs to the globus pallidus and the substantia nigra in the rat:
Light and electron microscopic studies using PHA-L methods. J Comp Neurol 260:435–452
Kitamura M, koshikawa N, Yoneshige N, Cools AR (1999) Behavioral and neurochemical effects of
cholinergic and dopaminergic agonists administered into the accumbal core and shell in rats.
Neuropharmacology 38:1397-1407
Kiyatkin EA (1995) Functional significance of mesolimbic dopamine. Neurosci Biobehav Rev 19:573-
598
Koch M, Bubser M (1994) Deficient sensorimotor gating after 6-hydroxydopamine lesions of the rat
medial prefrontal cortex is reversed by haloperidol. Eur J Neurosci 6:1837-1845
Koch M (1996) The septo-hippocampal system is involved in prepulse inhibition of the acoustic startle
response in rats. Behav Neurosci 110:468–493
Koch M, Schnitzler H U (1997) The acoustic startle response in rats: circuits mediating evocation,
inhibition and potentiation. Behav Brain Res 89:35–49
Koch M (1999) The neurobiology of startle. Prog in Neurobiology 59:107-128
Kodsi MH, Swerdlow NR (1994) Quinolinic acid lesions of the ventral striatum reduce sensorimotor
gating of acoustic startle in rats. Brain Res 643:59-65
Kodsi MH, Swerdlow NR (1995) Prepulse inhibition in the rat is regulated by ventral and caudodorsal
striato-pallidal circuitry. Behav Neurocience 109:912-928
Kodsi MH, Swerdlow NR (1997) Regulation of prepulse inhibition by ventral pallidal projections Brain
Res Bull 43:219-228
Koester J (1991) Voltage-geared channels and the generation of the action potential. In: Kandel ER,
Schwartz JH, Jessell TM (Eds) Principles of Neural Science. Elsevier Science Publishers, New York,
pp 104-118
Kolb B, Whishaw Q (1990) Fundamentals of human neuropsychology, Chapter 6: The neurological
exam and clinical tests. Freeman and Company, New York, pp 115-129
Koshikawa N, Yoshida Y, Kitamura M, Saigusa T, Kobayashi M, Cools AR (1996) Stimulation of
acetylcholine or dopamine receptors in the nucleus accumbens differentially alters dopamine release
in the striatum of freely moving rats. Eur J Pharmacol 303:13-19
Kumari V, Checkley SA, Gray JA (1996) Effect of cigarette smoking on PPI of the acoustic startle reflex
in healthy male smokers. Psychopharmacology 128:54-60
Kumari V, Gray JA (1999) Smoking withdrawal, nicotine dependence and PPI of the acoustic startle
reflex. Psychopharmacology 141:11-15
Kumari V, Soni W, Sharma T (1999) Normalization of information processing deficits in schizophrenia
with clozapine. Am J Psychiatry 156:1046-1051
Lamberti JS, Schwarzkopf SB, Boutros N, Crilly JF, Martin R (1993) Within-session changes in sensory
gating assessed by P50 evoked potentials in normal subjects. Prog Neuropsychopharmacol Biol
Psychiatry 17:781-791
Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory roles.
Physiol Rev 71:155-233
Leitner DS, Cohen ME (1985) Role of the inferior colliculus in the inhibition of acoustic startle in the
rat. Physiol Behav 34:65-70
Lennartz RC, Weinberger NM (1992) Frequency selectivity is related to temporal processing in parallel
thalamocortical auditory pathways. Brain Res 583:81-92.
Light GA, Malaspina D, Geyer MA, Luber BM, Coleman EA, Sackeim HA, Braff DL (1999) Amphetamine
disrupts P50 suppression in normal subjects. Biol Psychiatry 46:990-996
Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL (2000) Normal P50 suppression in
schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 157:767-
771.
Light GA, Braff DL (2000) Do self-reports of perceptual anomalies reflect gating deficits in
schizophrenia patients? Biol Psychiatry 47:463-467
Logue SF, Owen EH, Rasmussen DL, Wehner JM (1997) Assessment of locomotor activity, acoustic
and tactile startle, and PPI of startle in inbred mouse strains and F1 hybrids: implications of genetic
background for single gene and quantitative trait loci analyses. Neuroscience 80:1075-1086
Luntz-Leybman V, Bickford PC, Freedman R (1992) Cholinergic gating of response to auditory stimuli
in rat hippocampus. Brain Res 587:130-136
Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in
the rat. Psychopharmacology 94: 507–514
Mansbach RS (1991) Effects of NMDA receptor ligands on sensorimotor gating in the rat. Eur J
Pharmacol 202:61–66
Mansbach RS, Geyer MA (1991) Parametric determinants in prestimulus modification of acoustic
startle: interaction with ketamine. Psychopharmacology 105:162–168
Mansbach RS, Brooks EW, Sanner MA, Zorn SH (1998) Selective dopamine D4 receptor antagonists
reverse apomorphine-induced blockade of PPI. Psychopharmacology 135:194-200
McGhie A, Chapman J (1961) Disorders of attention and perception in early schizophrenia. Br J Med
Psychol 34:103–116
Mednick SA, Machon RA, Huttunen MO, Bonnett D (1988) Adult schizophrenia following prenatal
exposure to an influenza epidemic. Arch Gen Psychiatry 45:189-192
Meridith GE, Pattiselanno A, Groenewegen HJ, Haber SN (1996) Shell and core in monkey and human
nucleus accumbens identified with antibodies to calbindin-D28k. J Comp Neurol 365:628-639
Metrakos JD, Metrakos K (1970) Genetic factors in epilepsy. In: Niedermeyer E (Eds) Modern
Problems Pharmacopsychiatry 4:71-86
48

Miller CL, Bickford PC, Luntz-Leybman V, Adler LE, Gerhardt GA, Freedman R (1992) Phencyclidine
and auditory sensory gating in the hippocampus of the rat. Neuropharmacology 31:1041-1048
Miller CL, Freedman R (1995) The activity of hippocampal interneurons and pyramidal cells during the
response of the HPC to repeated auditory stimuli. Neuroscience 69: 371–381
Miyazato H, Skinner RD, Reese NB, Mukawa J, Garcia-Rill E (1996) Midlatency auditory evoked
potentials and the startle response in the rat. Neuroscience 75: 289–300
Mogenson GJ (1987) Limbic-motor integration. Prog Psychobiol Physiol Psychol, pp 117-170
Morton N, Ellis C, Gray NS, Toone BK, Leigh PN, Chaudhuri KR (1995) The effects of apomorphine and
L-dopa challenge on prepulse inhibition in patients with Parkinson's disease. Schizophr Res 15:181-
182
Moxon KA, Gerhardt GA, Bickford PC, Austin K, Rose GM, Woodward DJ, Adler LE (1999) Multiple
single units and population responses during inhibitory gating of hippocampal auditory response in
freely-moving rats. Brain Res 825:75-85.
Naatanen R, Picton T (1987) The N1 wave of the human electric and magnetic response to sound: a
review and an analysis of the component structure. Psychophysiology 41:585-601
Naber G, Kathman N, Engel RR (1992). P50 suppression in normal subjects: influence of stimulus
intensity, test repetition, and presentation mode. J Psychophysiol 6:47-53
Nagamine M, Tomisawa K (1999b) A selective dopamine D4 receptor antagonist, NRA0160: a
preclinical neuropharmacological profile. Life Sci 65:2109-2125
Nagamoto HT, Adler LE, Waldo MC, Freedman R (1989) Sensory gating in schizophrenics and normal
controls: effects of changing stimulation interval. Biol Psychiatry 25:549-561.
Nagamoto HT, Adler LE, Waldo MC, Griffith J, Freedman R (1991) Gating of auditory response in
schizophrenics and normal controls: Effects of recording site and stimulation interval on the P50
wave. Schizophr Research 4:31-40
Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R (1996) Gating of auditory P50 in
schizophrenics: Unique effects of clozapine. Biol Psychiatry 40:181-188
Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, Hea R, Griffith J (1999) Auditory
P50 in schizophrenics on clozapine: improved gating parallels clinical improvement and changes in
plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology 39:10-17
Nakanishi H, Kita H, Kitai ST (1988) An N-methyl-D-aspartate receptor mediated excitatory
postsynaptic potential evoked in subthalamic neurons in an in vitro slice preparation in the rat.
Neurosci Lett 95:130–136
Nehlig A (1999) Does caffeine lead to psychological dependence? Chemtech 29:30-35
Nuechterlein KH, Dawson ME (1994). Chapter 117. Neurophysiological and psychophysiological
approaches to schizophrenia and its pathogenesis. In: Psychopharmacology: the Fourth generation
of progress. FE Bloom, DJ Kupfer, BS Bunney, RD Ciaranello, KL Davis, GF Koob, HY Meltzer, CR
Schuster, RI Shader, SJ Watson (Eds). Lippincott, Williams & Wilkins, USA
Newman DB, Ginsberg CY (1994). Reticular nuclei that project to the thalamus in rats: A retrograde
tracer study. Brain Behav Evol 44:1-39.
Oades RD (1985) The role of noradrenaline in tuning and dopamine in switching between signals in
the CNS. Neurosc Biobehav Rev 8:261-282
Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Kumagai T, Nakazato A, Nagamine M,
Yamaguchi K, Tomisawa K (1999a) The atypical antipsychotic profile of NRA0045, a novel dopamine
D4 and 5-hydroxytryptamine2A receptor antagonist, in rats. Br J Pharmacol 121:515-525
Okuyama S, Kawashima N, Chaki S, Yoshikawa R, Funakoshi T, Ogawa SI, Suzuki Y, Ikeda Y;
Kumagai T, Nakazato A, Ott DA, Mandel RJ (1995) Amphetamine sensitivity in open-field activity vs.
the PPI paradigm. Brain Res Bull 37:219-222
Patterson JV, Jin Y, Gierczak M, Hetrick WP, Potkin S, Bunney WE, Sandman CA (2000) Effects of
temporal variability on P50 and the gating ratio in schizophrenia. Arch Gen Psychiatry 57:64
Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic Press Ltd, London
Paylor R, Crawley JN (1997) Inbred strain differences in PPI of the mouse startle response.
Psychopharmacology 132:169-180
Peng RY, Mansbach RS, Braff DL, Geyer MA (1990) A D2 dopamine receptor agonist disrupts
sensorimotor gating in rats. Implications for dopaminergic abnormalities in schizophrenia.
Neuropsychopharmacology 3: 211-218
Perry W, Braff DL (1994) Information processing deficits and thought disorder in schizophrenia. Am J
Psychiatry 151:363-367
Perry W, Geyer MA, Braff DL (1999) Sensorimotor gating and thought disturbance measured in close
temporal proximity in schizophrenic patients. Arch Gen Psychiatry 56:277-281
Peeters BWMM, Van Rijn CM, Vossen JMH, Coenen AML (1989a) Effects of GABA-ergic agents on
spontaneous non-convulsive epilepsy, EEG and behavior in the WAG/Rij inbred strain of rats. Life
Sci 45: 1171-1176
Peeters BWMM, Van Rijn, Van Luijtelaar ELJM, Coenen AML (1989b) Antiepileptic and behavioral
actions of MK-801 in animal model of spontaneous absence epilepsy. Epilepsy Res 3:178-181
Peeters BWMM, Kerbusch JML, Van Luijtelaar ELJM, Vossen JMH, Coenen AML (1990a) Genetics of
absence epilepsy in rats. Behav Genetics 20:453-262
Peeters BWMM, Van Rijn CM, Vossen JHM, Coenen AML (1990b) Involvement of NMDA receptors in
non-convulsive epilepsy in WAG/Rij rats. Life Sci 47:523-529
Pickar D, Litman RE, Konicki PE, Wolkowitz OM, Breier A (1990) Neurochemical and neural
mechanisms of positive and negative symptoms in schizophrenia. Modern Problems
Pharmacopsychiatry 24:124-151
49

Pickles J O (1981) An introduction to the physiology of hearing. New York: Harcourt Brace Jovanovich.
Pijnenburg AJ, Van Rossum JM (1973) Letter: Stimulation of locomotor activity following injection of
dopamine into the nucleus accumbens. J Pharmacol 25:1003-1005
Pijnenburg AJ, Honig WM, Boudier HA, Cools AR, Van der Heyden JA, Van Rossum (1976) Further
investigation on the effects of ergometrine and other ergot derivates following injection into the
nucleus accumbens in the rat. Arch Int Pharmacodyn Ther 222:103-115
Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine
preferentially increase extracellular dopamine in the shell as compared with the core of the rat
nucleus accumbens. Proc Natl Acad Sci USA 92:12304-12308
Powell EW, Hatton JB (1969). Projections of the inferior colliculus in the cat. J Comp Neurol 136:183-
192
Prinssen EPM, Balestra, Bemelmans FFJ, Cools AR (1994) Evidence for a role of the shell of the
nucleus accumbens in oral behavior of freely moving rats. J Neuroscience 14:1555-1562
Pulvirenti L, Swerdlow NR, Hubner CB, Koob GF (1991) The role of limbic-pallidal circuitry in the
activating and reinforcing properties of psychostimulant drugs. In: Willner P, Scheel-Krüger J (Eds)
The mesolimbic dopamine system: from motivation to action. John Wiley & Sons, New York, pp 131-
140
Ralph RJ, Varty GB, Kelly MA, Wang YM, Caron MG, Rubinstein M, Grandy DK, Low MJ, Geyer MA
(1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of
prepulse inhibition produced by amphetamine in mice. J Neurosci 19:4627-4633.
Reijmers LGJE, Peeters BWMM (1994a) Acoustic prepulses can facilitate the startle reflex in rats:
discrepancy between rat and human data resolved. Brain Res Bull 35:337–338
Reijmers LGJE, Peeters BWMM (1994b) Effects of acoustic prepulses on the startle reflex in rats: a
parametric analysis. Brain Res 667: 143–159
Reijmers LGJE, Vanderheyden PML, Peeters BWMM (1995) Changes in prepulse inhibition after local
administration of NMDA receptor ligands in the core region of the rat nucleus accumbens. Eur J
Pharmacol 272: 131–138
Reite M, Teale P, Zimmerman J, Davis K, Whalen J (1988) Source location of a 50 msec latency
auditory evoked field component. Electroenceph Clin Neurophysiol 70:490-498
Rigdon GC (1990) Differential effects of apomorphine on PPI of acoustic startle reflex in two rat
strains. Psychopharmacology 102:419-421
Rigdon GC, Weatherspoon JK (1992) 5-Hydroxytryptamine 1A receptor agonists block prepulse
inhibition of the acoustic startle response. J Pharmacol Exp Ther 263:486-493
Roozendaal B, Cools AR (1994) Influence of the noradrenergic state of the nucleus accumbens in
basolateral amygdala mediated changes in neophobia of rats. Behav Neurosci 108:1107-1118.
Rots NY, Cools AR, Berod A, Voorn P, Rostene W, de Kloet ER (1996) Rats bred for enhanced
apomorphine susceptibility have elevated tyrosine hydroxylase mRNA and dopamine D2-receptor
binding sites in nigrostriatal and tuberoinfundibular dopamine systems. Brain Res 710:189-196
Schaefer GJ, Michael RP (1987) Ethanol and current thresholds for brain self-stimulation in the lateral
hypothalamus of the rat. Alcohol 4: 209-213
Schwarzkopf SB, Mitra T, Bruno JP (1992) Sensory gating in rats depleted of DA as neonates:
potential relevance to findings in schizophrenic patients. Biol Psychiatry 31:759-773
Schwarzkopf SB, Lamberti JS, Smith DA (1993a) Concurrent assessment of acoustic startle and
auditory P50 evoked potential measures of sensory inhibition. Biol Psychiatry 33:815–828
Schwarzkopf SB, Bruno JP, Mitra T (1993b) Effects of haloperidol and SCH 23390 on acoustic startle
and PPI under basal and stimulated conditions. Prog Neuropsychopharmacol Biol Psychiatry
17:1023-1036
Schwarzkopf SB, McCoy L, Smith DA, Boutros NN (1993c) Test-retest reliability of prepulse inhibition
of the acoustic startle response. Biol Psychiatry 34:896-900
Sibley and Monsma (1992) Molecular biology of dopamine receptors. TIPS 13:61
Siegel C, Waldo M, Mizner G, Adler LE, Freedman R (1984) Deficits in sensory gating in schizophrenic
patients and their relatives. Arch Gen Psychiatry 41:607-612
Sills TL (1999) Amphetamine dose dependently disrupts PPI of the acoustic startle response in rats
within a narrow time window. Brain Res Bull 48:445-448
Simpson G V, Knight R T (1993) Multiple brain systems generating the rat auditory evoked potential.
II. Dissociation of auditory cortex and non-lemniscal generator systems. Brain Res 602:251-263
Sipes TA, Geyer MA (1994) Multiple serotonin receptor subtypes modulate prepulse inhibition of the
startle response in rats. Neuropharmacology 33:441-448
Sipes TE, Geyer MA (1997) DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in
the ventral pallidum. Brain Res 761:97-104.
Smith Y, Bolam JP, Krosigk MV (1990) Topographical and synaptic organization of the GABAcontaining
pallidosubthalamic projection in the rat. Eur J Neurosci 2: 500–511
Snyder SH (1976) The dopamine hypothesis of schizophrenia: focus on the dopamine receptor. Am J
Psychiatry, 133:197-202
Somogyi P, Bolam JP, Totterdell S, Smith AD (1981) Monosynaptic input from the nucleus accumbensventral
striatum region to retrogradely labeled nigrostriatal neurons. Brain Res 217:245-263
Somogyi P, Bolam JP, Smith AD (1981) Monosynaptic cortical input and local axon collaterals of
identified striatonigral neurons. A light and electron microscopic study using the Goldi-peroxidasedegeneration
procedure. J Comp Neurol 195: 567–584
50

Squires NK, Ollo C (1986) Human evoked potential techniques: possible appications to
neuropsychology. In: HJ Hannay (Eds) Experimental Techniques in Human Neuropsychology. Oxford
University Press, New York
Starr A, Aguinaldo T, Roe HJ, Michalewski HJ (1997) Sequential changes of auditory processing during
target detection: Motor responding versus mental counting. Electroenceph Clin Neurophysiol
105:201-212
Steiner H, kitai ST (2000) Regulation of rat cortex function by D1 dopamine receptors in the striatum.
J Neurosci 20:5449-5460
Steriade M, Llinas RR (1988) The functional states of the thalamus and the associated neuronal
interplay. Physiol Rev 68:649-742
Stevens KE, Fuller LL, Rose GM (1991) Dopaminergic and noradrenergic modulation on amphetamineinduced
changes in auditory gating. Brain Res 555:91–98
Stevens KE, Luthman J, Lindqvist EVA, Johnson RG, Rose GM (1996) Effects of neonatal dopamine
depletion on sensory inhibition in the rat. Pharmacol Biochem Behav 53:817–823
Stevens KE, Johnson RG, Rose GM (1997) Rats reared in social isolation show schizophrenia-like
changes in auditory gating. Pharmacol Biochem Behav 58:1031-1036
Stevens KE, Wear KD (1997) Normalizing effects of nicotine and a novel nicotinic agonist on
hippocampal auditory gating in two animal models. Pharmacol Biochem Behav 57:869-874
Stevens KE, Nagamoto H, Johnson RG, Adams CE, Rose GM (1998) Conic acid lesions in adult rats as
a model of schizophrenia: changes in auditory information processing. Neuroscience 82: 701–708
Strange (1996) Dopamine receptors: studies on their structure and function. Adv Drug Res 28:315
Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: A combined
fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321-353
Swerdlow NR, Vaccarino F, Amalric M, Koob G (1986) Neural substrates for the motor-activating
properties of psychostimulants: a review of recent findings. Pharmacol Biochem Behav 25:233-248
Swerdlow NR, Koob GF (1987) Dopamine, schizophrenia, mania, and depression: Toward a unified
hypothesis of cortico-striato-pallido-thalamic function. Behav Brain Science 10:197-245
Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990a) Amphetamine
disruption of PPI of acoustic startle is reversed by depletion of mesolimbic dopamine.
Psychopharmacology 100:413-416
Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990b) Schizophrenia-like sensorimotor gating
abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacology
101:414-420
Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991) Effects of spiperone, raclopride, SCH 23390 and
clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. J
Pharmacol Exp Ther 256:530-256
Swerdlow NR, Caine SB, Geyer MA (1992a) Regionally selective effects of intracerebral dopamine
infusion on sensorimotor gating of the startle reflex in rats. Psychopharmacology 108:189-195
Swerdlow NR, Caine SB, Braff DL, Geyer MA (1992b) Neural substrates of sensorimotor gating of the
startle reflex: a review of recent findings and their implications. J Psychopharmacol 6: 176–190
Swerdlow et al (1992) {local NAC GLU}
Swerdlow NR, Benbow CH, Zisook S, Geyer MA, Braff DL (1993). A preliminary assessment of
sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33:298-301
Swerdlow NR, Zisook D, Taaid N (1994) Seroquel (ICI 204,636) restores PPI of acoustic startle in
apomorphine-treated rats: Similarities to clozapine. Psychopharmacology 114:675-678
Swerdlow NR, lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA (1995a). Increased sensitivity
to the gating-disruptive effects of apomorphine after lesions of the medial prefrontal cortex or
ventral hippocampus in adult rats. Psychopharmacology 122:27-34
Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR (1995b) Impaired prepulse
inhibition of acoustic and tactile startle response in patients with Huntington’s disease. J Neurol
Neurosurg Psychiatry 58:192-200
Swerdlow NR (1996) Cortico-striatal substrates of cognitive, motor, and sensory gating: speculations
and implication for psychological function and dysfunction. Adv Biol Psychiatry 2:179-207
Swerdlow NR, Varty GB, Geyer MA (1998a) Discrepant findings of clozapine effects on PPI of startle: is
it the route or the rat? Neuropsychopharmacology 18:50-56
Swerdlow NR, Geyer MA (1998b) Using an animal model of deficient sensorimotor gating to study the
pathophysiology and new treatments of schizophrenia. Schizophrenia Bull 24:285-301
Swerdlow NR, Braff DL, Geyer MA (2000) Animal models of deficient sensory gating: what we know,
what we think we know, and what we hope to know soon. Behav Pharmacol 11:185-204
Taber MT, Fibiger HC (1995) Electrical stimulation of the prefrontal cortex increases dopamine release
in the nucleus accumbens of the rat: modulation by metabotropic glutamate receptors. J Neurosci
15:3896-904
Tamminga CA (1998) Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21-36
Van den Bos R, Cools AR (1989) The involvement of the nucleus accumbens in the ability of rats to
switch cue-directed behaviors. Life Sci 44:367-379
Van den Bos R, Charria-Ortiz GA, Bergmans AC, Cools AR (1991) Evidence that dopamine in the
nucleus accumbens is involved in the ability of rats to switch to cue-directed behaviors. Behav Brain
Res 42:107-114.
Van Luijtelaar ELJM, Coenen AML (1986). Two types of electrocortical paroxysms in an inbred strain of
rats. Neuroscience Lett 70:393-397
51

Van Luijtelaar ELJM, Coenen AML (1989). The WAG/Rij model for generalized absence epilepsy. Adv
Epileptology 17:16-21
Van Luijtelaar ELJM, Coenen AML (1997). The WAG/Rij rat model of absence epilepsy: ten years of
research (A compilation of papers). Nijmegen University Press, Nijmegen, The Netherlands
Van Luijtelaar EL, Miller CA, Coenen AM, Drinkenburg WH, Ellenbroek BA (1998) Differential effects of
non-REM and REM sleep on sensory gating in rats. Acta Neurobiologiae experimentalis 58:263-270
Van Luijtelaar G, Fabene PF, De Bruin N, Jongema C, Ellenbroek BA, Veening JG (submitted) Is the
lateral septum involved in sensory gating in rats? A Fos study
Varty GB, Higgins GA (1995) Examination of drug-induced and isolation-induced disruptions of PPI as
models to screen antipsychotic drugs. Psychopharmacology 122:15-26
Varty GB, Ralph RJ, Geyer MA (1997) Apomorphine and phencyclidine disrupt prepulse inhibition and
fear-potentiated startle using a combined paradigm. Soc Neurosci Abstr 23:1363
Varty GB, Higgins GA (1998) dopamine agonist-induced hypothermia and disruption of PPI: evidence
for a role of D3 receptors? Behav Pharmacol 9:445-455
Varty GB, Braff DL, Geyer MA (1999a) Is there a critical developmental 'window' for isolation rearinginduced
changes in PPI of the acoustic startle response? Behav Brain Res 100:177-183
Varty GB, Marsden CA, Higgins GA (1999b) Reduced synaptophysin immunoreactivity in the dentate
gyrus of PPI-impaired isolation-reared rats. Brain Res 824:197-203
Vaughan HG, Arezzo JC (1988) The neural basis of event-related potentials. In: TW Picton (Eds)
Human Event-Related Potentials EEG Handbook (revised series, vol. 3). New York: Elsevier, pp 45-
96
Veening JG, Cornelissen FM, Lieven PAJM (1980) The topical organization of the afferents to the
caudate-putamen of the rat: a horseradish peroxidase study. Neuroscience 5:1253-1268
Voorn P, Groenewegen H, Gerfen DR (1989) Compartmental organization of the ventral striatum of
the rat: immunohistochemical distribution of enkephalin, substance P, dopamine, and calciumbinding
protein. J Comp Neurol 289:189–201
Wadenberg MG, Sills TL, Fletcher PJ, Kapur S (2000) Antipsychotic-like effects of amoxapine, without
catalepsy, using the PPI of the acoustic startle reflex test in rats. Biol Psychiatry 47:670-676
Waldo MC, Freedman R (1986) Gating of auditory evoked responses in normal college students.
Psychiatry Res 19:233-239
Waldo MC, Adler LE, Freedman R (1988) Defects in auditory sensory gating and their apparent
compensation in relatives of schizophrenics. Schizophr Res 1:19-24
Waldo MC, Carey G, Myles-Worsley M, Cawthra E, Adler LE, Nagamoto HT, et al (1991) Codistribution
of a sensory gating deficit and schizophrenia in multi-affected families. Psychiatry Res 39:257-68
Waldo M, Myles Worsley M, Madison A, Byerley W, Freedman R (1995) Sensory gating deficits in
parents of schizophrenics. Am J Med Genet 60:506-511
Waldo MC, Cawthra E, Adler LE, Dubester S, Staunton M, Nagamoto H, Baker N, Madison A, Simon J,
Scherzinger A, et al (1994) Auditory sensory gating, hippocampal volume, and catecholamine
metabolism in schizophrenics and their siblings. Schizophr Res 12:93-106
Wan FJ, Swerdlow (1993) Intra-accumbens infusion of quinpirole impairs sensorimotor gating of
acoustic startle in rats Psychopharmacology 113:103-109
Wan FJ, Geyer MA, Swerdlow NR (1994) Accumbens D2 modulation of sensorimotor gating in rats:
Assessing anatomical localization. Pharmacol Biochem Behav 49:155-163
Wan FJ, Geyer MA, Swerdlow NR (1995) Presynaptic dopamine-glutamate interactions in the nucleus
accumbens regulate sensorimotor gating. Psychopharmacology 120:433-441
Wan FJ, Swerdlow NR (1996a) Sensorimotor gating in rats is regulated by different dopamineglutamate
interaction in the nucleus accumbens core and shell subregions. Brain Res 722:168-176
Wan FJ, Taaid N, Swerdlow NR (1996b) Do D1/D2 interactions regulate PPI in rats?
Neuropsychopharmacology 14:265-274
Wan FJ, Swerdlow NR (1997) The basolateral amygdala regulates sensorimotor gating of acoustic
startle in the rat. Neuroscience 76:715-724
Watson CG, Kucala T, Tilleskjor C, Jacobs L. Schizophrenic birth seasonality in relation to incidence of
infectious diseases and temperature extremes. Arch Gen Psychiatry 41:85-90
Weike AI, Bauer U, Hamm AO (2000) Effective neuroleptic medication removes prepulse inhibition
deficits in schizophrenic patients. Biol Psychiatry 47:61-70
Weinberger NM, Diamond DM (1988) Dynamic Modulation of the Auditory System by Associative
Learning. In: Auditory Function: neurological bases of hearing, GM Edelman, WE Gall, WM Cowan
(Eds). The Neuroscience Institute (John Wiley & Sons), New York, pp 485-512
Wiley JL (1994) Clozapine’s effects on phencyclidine-induced disruption of prepulse inhibition of the
acoustic startle response. Pharmacol Biochem Behav 49:1025–1028
Wilkinson LS, Killcross SS, Humby T, Hall FS, Geyer MA, Robbins TW (1994) Social isolation in the rat
produces developmentally specific deficits in PPI of the acoustic startle response without disrupting
latent inhibition. Neuropsychopharmacology 10:61-72
Williams DJ, Crossman AR, Slater P (1977) The efferent projections of the nucleus accumbens in the
rat. Brain Res 130:217-227
Williams MN, Faull RLM (1985) The striatonigral projection and nigrotectal neurons in the rat: A
correlated light and electron microscopic study demonstrating a monosynaptic striatal input to
identified nigrotectal neurons using a combined degeneration and horseradish peroxidase
procedure. Neuroscience 14:991-1010
Wilson CJ (1987) Morphology and synaptic connections of crossed corticostriatal neurons in the rat. J
Comp Neurol 263:567–580
52

Winer JA (1985) The medial geniculate body of the cat. Adv Anat Embryol Cell Biol 86:1-97
Winer JA (1992) The Functional Architecture of the Medial Geniculate Body and the Primary Auditory
Cortex. In: The Mammalian Auditory Pathway: neuroanatomy, DB Webster, AN Popper, RR Fay
(Eds). Springer-Verlag, New York, pp 222-409
Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469-492
Wise RA, Rompré PP (1989) Brain dopamine and reward. Ann Rev Psychol 40:191-225
Witter MP (1989) Connectivity of the rat hippocampus. In: V Chan-Palay, C Köhler (Eds), Neurology
and Neurobiology, Vol. 52. The hippocampus: New Vistas. Alan R Liss, New York, pp 53-69
Woods CC, Wolpaw JR (1982) Scalp distribution of human auditory evoked potentials. II Evidence for
overlapping sources and involvement of auditory cortex. Electroenceph Clin Neurophysiol 54:25-38
Woods DL, Knight RT, Neville HJ (1984) Bitemporal lesions dissociate auditory evoked potentials and
perception. Electroenceph Clin Neurophysiol 57:208-220
Woods DL, Clayworth CC, Knight RT, Simpson GV, Naeser MA (1987) Generators of middle and long
latency auditory evoked potentials: Implications from studies of patients with bitemporal lesions.
Electroenceph Clin Neurophysiol 68:132-148
Woolf NJ, Harrison JB, Buchwald JS (1990). Cholinergic neurons of the feline pontomesencephalon: II.
Ascending anatomical projections. Brain Res 520:55-72.
Wu MF, Krueger J, Ison JR, Gerrard RL (1984) Startle reflex inhibition in the rat: its persistence after
extended repetition of the inhibitory stimulus. J Exp Psychology: Animal Behav Processes 10:221-
228
Wu MF, Jenden DJ, Fairchild MD, Siegel JM (1993) Cholinergic mechanisms in startle and PPI: effects
of the false cholinergic precursor N-aminodeanol. Behav Neurosci 107:306-316
Yee BK (2000) Cytotoxic lesions of the medial prefrontal cortex abolishes the partial reinforcement
extinction effect, attenuates prepulse inhibition of the acoustic startle reflex and induces transient
hyperlocomotion, while sparing spontaneous object recognition memory in the rat. Neuroscience
95:675-689
Young KA, Randopaminell PK, Wilcox RE (1991) Dose and time response analysis of apomorphine's
effect on PPI of acoustic startle. Behav Brain Res 42:43-48
Young KA, Randopaminell PK, Wilcox RE (1995) Startle and sensorimotor correlates of ventral
thalamic dopamine and GABA in rodents. Neuroreport 6:2495-2499
Zahm DS, Brog JS (1992) On the significance of subterritories in the accumbens part of the ventral
striatum. Neuroscience 50:751-767
Zahm DS (1999) Functional-anatomical implications of the nucleus accumbens core and shell
subterritories. Adv Ventral Striatum Extended Amygdala 877:133-128
Zhang J, Engel JA, Ericson M, Svensson L (1999) Involvement of the medial geniculate body in
prepulse inhibition of acoustic startle. Psychopharmacology 141:189-196
Zhang J, Forkstam C, Engel JA, Svensson L (2000) Role of dopamine in prepulse inhibition of acoustic
startle. Psychopharamcology 149:181-188
Zavitsanou K, Cranney J, Richardson R (1999) dopamine antagonists in the orbital prefrontal cortex
reduce PPI of the acoustic startle reflex in the rat. Pharmacol Biochem Behav 63:55-61
Zouridakis G, Boutros N (1992) Stimulus parameter effects on the P50 evoked response (Brief
Report). Biol Psychiatry 32:839-884
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The goal of the present thesis was to analyze (1) to what
extent the various dopaminergic subsystems in the brain
are involved in information processing assessed in the PPI
and AEP gating paradigms and (2) to what extent these
paradigms represent similar or different aspects of
information processing.
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8.1 RAT GENOTYPES WITH DIFFERENCES IN DA PROPERTIES
One of the important goals of the present thesis was to analyze to what
extent the various DA subsystems in the brain are involved in information
processing assessed in the PPI and AEP gating paradigms. Several arguments
have been presented in the introduction (Chapter 1) that indicate that the
nigrostriatal DA system and mesolimbic DA system interact and therefore we
have posed the question in what way this balance between both systems is
involved in different functions of DA in the brain. A non-invasive way of
investigating effects of such a balance is to compare rat genotypes that show
opposite DA properties. Therefore, we have decided to study the possible
differences in four rat genotypes (APO-SUS, APO-UNSUS, WAG/Rij and ACI)
before and after administration of the DA antagonist haloperidol on SWD
(Chapter 3) and gating mechanisms (Chapter 5), which have been proposed
to be dependent on DA. These genotypes have been introduced in Chapter 1.
In the study in Chapter 4, we have determined the differences in DA
properties between the four genotypes.
Results from Chapters 3-5 and earlier studies are summarized in Table
8.1. These data are further discussed in this section.
Table 8.1 Rat genotypes: DA properties, SWD incidence and information
processing
Rat genotypes APO- APO- WAG/Rij ACI
SUS UNSUS
� Apomorphine-induced gnawing + ⎯ ⎯ /(+) ⎯
(1,2,CH 4) � DA ractivity
nigrostriatal system
⎯ + (⎯ )/+ +
� Novelty/amphetamine-induced
locomotor stimulation (1,3,CH 4) �
+ ⎯ + ⎯
DA reactivity mesolimbic system + ⎯ + ⎯
� TH mRNA (SNc), D2/3 binding sites
(CPu), D1 receptor mRNA (CPu) (4)
+ ⎯ ? ?
� SWDs (baseline and haloperidol)
(5,6,CH 3)
+ + ⎯ + ⎯
� Prepulse inhibition (PPI) (7,CH 5) ⎯ + + +
� Startle reactivity (7,CH 5) + ⎯ ⎯ +
� AEP (N50) gating (CH 5) + + ⎯ +
+ relatively high; ⎯ relatively low; CH= Chapter (REFERENCES 1=Cools et al 1990, 2=Ellenbroek et
al 2000, 3=Cools et al 1997, 4=Rots et al 1996, 5=Inoue et al 1990, 6=Cools and Peeters 1992,
7=Ellenbroek et al 1995)
8.1.1 DOPAMINE AND SPIKE-WAVE DISCHARGES (SWDS)
SWDs are thought to be due to synchronized responses of thalamo-cortical
(TC) neurons. This synchronization process is considered to be caused by
GABA-mediated output from the reticular thalamic nucleus (RTN) to TC relay
cells (Steriade and Llinas 1988).
Buzsáki et al (1990b) have proposed that the SWD incidence is related
to differences in DA properties between rat strains. For instance, the Fisher
344 have more SWDs, a higher tyrosine hydroxylase (TH) activity and D2
binding values in the substantia nigra (SN) and dorsal striatum indicating
enhanced DA responsiveness for the nigrostriatal system as compared to
Buffalo rats (Buzsáki et al 1990b). This implies that a low nigrostriatal DA
121

activity is related to the occurrence of SWDs in these Fisher rats. Direct
evidence confirming this suggestion comes from studies in which an increase
in SWD incidence was found following injections of DA blockers
(chlorpromazine and acepromazine) into the dorsal striatum (Buzsáki et al
1990a) and lesioning of the SNc neurons with 6-OHDA) (Danober et al 1998).
Indirect evidence that underlines the role of striatal DA in SWD occurrence
comes from studies in which DA agents were systemically injected: DA
agonists decreased and DA antagonists increased SWD incidence (Avakyan
and Arushanyan 1976; Warter et al 1988; Buzsáki et al 1990a; Inoue et al
1994; Midzianovskaia 1998, 1999).
Cools and Peeters (1992) have assessed the occurrence of SWDs in the
APO-SUS and the APO-UNSUS selection lines and they have found that these
rats not only differ in their DA properties, but also in SWD incidence. APO-
SUS rats (six months old) have a higher SWD incidence and have been
characterized by a low DA activity of the nigrostriatal system versus a high
DA reactivity of the mesolimbic system as compared to the APO-UNSUS rats
(Cools et al 1990; Cools and Peeters 1992; Rots et al 1996). Another rat
genotype, the WAG/Rij, is considered as an animal model for generalized
absence epilepsy (Coenen et al 1991; Van Luijtelaar and Coenen 1986). ACI
rats often serve as a control rat strain for the WAG/Rij rats, since these rats
appear to be virtually free of SWDs (Inoue et al 1990). There is also an
indication that DA might play a modulatory role in the SWD incidence in
WAG/Rij rats, since the DA antagonist fluanisone has been shown to induce a
large increase in spike-wave activity in WAG/Rij's (Inoue et al 1994).
Given above mentioned considerations by Buzsáki et al (1990b) and
Cools and Peeters et al (1992) and the findings by Inoue et al (1994), it has
been suggested that certain DA properties in particular rat genotypes occur in
parallel with spike-wave phenomena in the EEG.
Chapter 3 presents the results of the study in which it was
investigated whether the four rat genotypes (APO-SUS, APO-
UNSUS, ACI and WAG/Rij) form a continuum with respect to the
incidence of SWDs at baseline and following injection with the
DA antagonist haloperidol. The DA properties of these rat
genotypes have already been described in chapter 4. This
presents the opportunity to analyze to what extent centain DA
properties are pathognomic for epileptic rats.
In agreement with previous reports (Inoue et al 1990; Cools and Peeters
1992), WAG/Rij's showed significantly more SWDs than ACI rats and APO-
SUS rats showed more SWDs compared to APO-UNSUS rats. Earlier data were
extended by the finding that the APO-SUS responded to a systemic injection
of haloperidol with an increase in SWD number and duration, in contrast to
the APO-UNSUS rats. It was suggested that haloperidol increases the SWD
incidence in APO-SUS rats by enlarging the relative dominance of the DA
reactivity in the mesolimbic system. In line with the expectations, the SWD
incidence was also enhanced following haloperidol in WAG/Rij’s compared to
the ACI rats. Finally, since the SWD incidence was higher in APO-SUS than in
WAG/Rij's during baseline and following haloperidol, it was hypothesized that
the relative dominance of the DA mesolimbic system is smaller in WAG/Rij
than in APO-SUS. However, further research was required to provide evidence
in favor of this hypothesis.
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Given the difference in SWD incidence in WAG/Rij’s and ACI rats and
the involvement of DA in SWDs, it was suggested that the WAG/Rij and ACI
strains might also differ in DA properties. In order to test whether the four rat
genotypes indeed differ in DA properties, the activity of the DA system in
various brain structures was established through assessment of behavioral
responses (Chapter 4). First, the DA activity in the dorsal striatum (caudateputamen,
CPu) was measured in a stereotypy paradigm. Secondly, novelty
induced spontaneous activity and amphetamine induced locomotor
stimulation was measured on an open-field to determine the DA reactivity in
the ventral striatum (nucleus accumbens, NAC). Non-epileptic ACI and APO-
UNSUS rats showed no response to apomorphine, indicating a high DA
activity of the nigrostriatal system (Cools et al 1990, Ellenbroek et al 2000,
Chapter 4). These rats also had a low locomotor responsiveness to
novelty/amphetamine, indicating a low DA reactivity of the mesolimbic
system (Cools et al 1990, 1997, Chapter 4). Epileptic WAG/Rij’s showed only
a small increase in gnawing following apomorphine and an increase in
locomotion in response to novelty/amphetamine on an open-field. Therefore,
WAG/Rij's are characterized by a high DA activity of the nigrostriatal system
versus a high DA reactivity of the mesolimbic system. Apomorphine-induced
gnawing was far more extensive in the epileptic APO-SUS and these rats have
also been shown to have high novelty/amphetamine-induced locomotion
(Cools et al 1990, 1997; Ellenbroek et al 2000, Chapter 4). It was concluded
that the DA activity of the nigrostriatal system in the WAG/Rij’s is higher than
in the APO-SUS but lower than in the ACI and APO-UNSUS rats. Finally, APO-
SUS and WAG/Rij rats have been suggested to posses a high DA reactivity of
the mesolimbic system as compared to the APO-UNSUS and ACI rats.
Given these findings, a model can be proposed that describes the
pathways via which DA could play a modulatory role in SWD incidence and
that could explain how the DA properties of the APO-SUS and WAG/Rij might
contribute to the high SWD incidence (see Figures 8.1-8.3).
The mechanism by which nigrostriatal DA has been proposed to
prevent the occurrence of SWDs is described by Buzsáki et al (1990a).
Normally, a sustained level of firing of DA neurons in the SNc provides a
steady inhibitory dorsal striatal (caudate-putamen, CPu) output, thereby
inhibiting the GABAergic projections from the substantia nigra pars reticulata
(SNr) and internal globus pallidus (GPi) to the thalamus. Evidence for such an
effect via the SNr has been provided by Depaulis et al (1988). They have
found a decrease in SWDs following suppression of SNr neurons by local
infusion of GABA-mimetic drugs. This leads to a disinhibition of TC neurons.
Disinhibition of TC neurons reduces the possibility of these neurons to show
synchronized responses thereby decreasing SWD incidence. According to the
apomorphine-induced gnawing data as presented in Chapter 4, it was
proposed that APO-SUS rats have a low DA activity in the nigrostriatal
pathway and therefore less disinhibition of TC neurons, in contrast to the
other genotypes. This could enhance the possibility of the TC neurons to show
synchronized responses and consequently increase SWDs in APO-SUS rats
(see pathway in Figure 8.1). Recently, it has been shown that injection of the
GABA antagonist picrotoxin in the SNr enhances SWDs (Deransart et al 2000)
which fits in well in the model in Figure 8.1.
Figure
8.1
SNc CPu SNr,GPi TC
DA↓
GABA ↓
GABA ↑
GLU
GLU
Cortex
SWD ↑
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Both the epileptic APO-SUS and WAG/Rij show a strong locomotor response
to novelty/amphetamine (Cools et al 1990, 1997; Chapter 4), indicating a
high DA reactivity in the mesolimbic system. Ventral striatal (nucleus
accumbens, NAC) DA was suggested to play a different role in SWD incidence
(Chapters 3-4). Two pathways were proposed via which a high DA reactivity
in the mesolimbic pathway could induce a high SWD incidence. First, it is
known that the NAC inhibits the SNc (Williams et al 1977; Somogyi et al
1981). Thus, DA activity in the NAC can inhibit the release of DA in the CPu
(Kohikawa et al 1996) and consequently enhance SWDs (see pathway in
Figure 8.2).
Figure
8.2
GABA ↑
SNc CPu SNr,GPi TC GLU
NAC core
DA↓
DA↑
GABA ↓
VTA
DA↑
GABA ↑
NAC shell
GLU
Cortex
SWD ↑
Secondly, Groenewegen et al (1999) have found evidence for a pathway from
the NAC shell to the ventral pallidum (VP) that projects to the RTN.
Synchronized responses of TC neurons that facilitate SWDs are considered to
be caused by GABA-mediated output from the RTN (Steriade and Llinas
1988). Therefore, it can be hypothesized that DA activation in the NAC could
result in disinhibition of the RTN via the VP thereby enhancing GABAergic
output from the RTN and increasing SWD incidence (see pathway in Figure
8.3). The VP has been implicated in the modulation of SWD incidence that is
in agreement with above-mentioned considerations. Injection of a GABA
antagonist in the VP has been shown to suppress SWDs (Deransart et al
1999).
Figure
8.3.
VTA
DA↑
NAC
shell VP
GABA ↑
GABA ↑
RTN
GABA ↓
TC
GLU
GLU
GLU
GLU
Cortex
SWD ↑
Deransart et al (2000) have found that injections of mixed DA D1/D2 or
selective D1 or D2 agonists in the NAC core region decreased SWDs, whereas
antagonists increased SWDs. These findings suggest that low instead of high
ventral striatal DA activity is related to the occurrence of SWDs. However,
effects of microinjections of DA agents in the NAC shell on SWD incidence
have not yet been investigated. Therefore, the findings by Deransart et al
(2000) do not exclude the possibility that the high DA reactivity in the ventral
striatum in the APO-SUS and WAG/Rij rats (Cools et al 1990, 1997; Chapter
4) could be related to the high SWD incidence in these rats, since the
mesolimbic DA modulation of SWDs in these rats could predominantly occur
via the NAC shell-VP-RTN projection as described in Figure 8.3. Further
studies remain to be done in order to test whether injecting a DA agonist into
124

the NAC shell or GABA agonists into the ventral pallidum enhance SWD
incidence.
Rots et al (1996) have performed in situ hybridization for the APO-SUS
and APO-UNSUS rats. They have found that APO-SUS rats that show
enhanced behavioral responsiveness to apomorphine have increased TH
transcription in SNc DA cells, elevated D1 receptor gene expression and
increased D2/D3 -receptor binding in the terminal area of the nigrostriatal
projection as compared to the APO-UNSUS. Since no such data are available
for the WAG/Rij's and ACI, we have decided to also perform in situ
hybridization for these rats. Biochemical analysis of the DA properties of the
rat genotypes is currently in progress in order to gain more insight into the
underlying mechanism involved in SWD incidence. Optical densities of DA D2
receptor mRNA, TH mRNA and DA transporter (DAT) mRNA for the
nigrostriatal and mesolimbic DA systems will be determined for the four rat
genotypes. Data from this study have not been presented in this thesis.
Main results and conclusions
Dopamine and spike-wave discharges Chapter 3
� In agreement with previous reports (Inoue et al 1990; Cools
and Peeters 1992), WAG/Rij's showed significantly more
SWDs than ACI rats and APO-SUS rats showed more SWDs
compared to APO-UNSUS rats.
� Earlier data were extended by the finding that the APO-SUS
responded to a systemic injection of haloperidol with an
increase in SWD number and duration, in contrast to the
APO-UNSUS rats. It was suggested that haloperidol
increases the SWD incidence in APO-SUS rats by enlarging
the relative dominance of the DA reactivity in the mesolimbic
system.
� In line with the expectations, the SWD incidence was also
enhanced following haloperidol in WAG/Rij’s compared to the
ACI rats.
� Finally, since the SWD incidence was higher in APO-SUS than
in WAG/Rij's during baseline and following haloperidol, it was
hypothesized that the relative dominance of the DA
mesolimbic system is smaller in WAG/Rij than in APO-SUS.
125

Main results and conclusions
Dopamine and genotypes Chapter 4
� Non-epileptic ACI and APO-UNSUS rats showed no response
to apomorphine, indicating a high DA activity of the
nigrostriatal system (Cools et al 1990, Ellenbroek et al 2000,
Chapter 4). These rats also had a low locomotor
responsiveness to novelty/amphetamine, indicating a low DA
reactivity of the mesolimbic system (Cools et al 1990, 1997,
Chapter 4).
� Epileptic WAG/Rij’s showed only a small increase in gnawing
following apomorphine and an increase in locomotion in
response to novelty/amphetamine on an open-field.
Therefore, WAG/Rij's are characterized by a high DA activity
of the nigrostriatal system versus a high DA reactivity of the
mesolimbic system.
� Apomorphine-induced gnawing was far more extensive in the
epileptic APO-SUS than in the remaining rat genotypes and
these rats have also been shown to have high
novelty/amphetamine-induced locomotion (Cools et al 1990,
1997; Ellenbroek et al 2000, Chapter 4).
� It was concluded that the DA activity of the nigrostriatal
system in the WAG/Rij’s is higher than in the APO-SUS but
lower than in the ACI and APO-UNSUS rats.
� Finally, APO-SUS and WAG/Rij rats have been suggested to
posses a high DA reactivity of the mesolimbic system as
compared to the APO-UNSUS and ACI rats.
8.1.2 DOPAMINE IN INFORMATION PROCESSING
DA agonists have been found to reduce PPI in both healthy human subjects
(Hutchison and Swift 1999; Abduljawad et al 1999) and in rats (Mansbach et
al 1988; Peng et al 1990; Swerdlow et al 1990a, 1990b, 1992). This effect
has been linked to a hyperactivity of DA at ventral striatal (e.g. nucleus
accumbens, NAC) D2 receptors (Swerdlow et al 1991; Wan and Swerdlow
1993; Wan et al 1994; Caine et al 1995; Ralph et al 1999). Furthermore, DA
infusion in the anteromedial dorsal striatum (caudate-putamen, CPu) has
been found to disrupt PPI (Swerdlow et al 1992). DA seems to play a
modulatory role in AEP gating as well. DA agonists such as bromocriptine and
amphetamine have been found to reduce P50 gating in healthy human
subjects (respectively, Adler et al 1994 and Light et al 1999). In rats,
amphetamine (1-1.83 mg/kg, IP) also interferes with the suppression of
cortical and hippocampal midlatency components, primarily by decreasing the
amplitude to S1 (Adler et al 1986, 1988; Bickford-Wimer et al 1990; Stevens
et al 1991; 1995, 1996; Johnson et al 1998; Chapter 7). In the study in
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Chapter 6 it was shown that activation of NAC DA D2 receptors by quinpirole
reduces cortical N40-N50 gating, an effect that was predominantly mediated
by its effects on the amplitude to S1. These effects could be prevented by
systemic pretreatment with the DA D2 antagonist haloperidol. So, these
studies show that DA plays a prominent role in PPI and is also involved in AEP
gating. Therefore, it was decided to study whether the four rat genotypes
with different DA properties as was shown in Chapter 4 would have
differences in these two gating paradigms in Chapter 5.
Several questions were asked in chapter 5: are PPI and AEP
gating disturbed in (a) rats that are marked by a relatively high
DA reactivity of the mesolimbic system, namely APOSUS and
WAG/Rij rats, or in (b) rats that are marked by a relatively high
DA activity of the nigrostriatal system, namely APO-UNSUS and
ACI rats? Furthermore, to what extent is a particular imbalance
between the DA nigrostriatal and mesolimbic system (c)
important in PPI and AEP gating deficits?
Ellenbroek et al (1995) have found that APO-SUS rats show diminished
PPI as compared to rats of the APO-UNSUS genotype. AEP gating has not yet
been studied in the APO-SUS and APO-UNSUS rats. One aim of the study in
Chapter 5 was to determine whether APO-SUS rats would also have a deficit
in AEP gating as compared to the APO-UNSUS. Another goal was to establish
if two other rat genotypes, the ACI and WAG/Rij rats would differ in PPI and
AEP-gating. Since the APO-SUS rats have a high DA reactivity in the ventral
striatum (Cools et al 1990) and given the findings that DA hyperactivity in the
ventral striatum has been implicated in both gating deficits (Swerdlow et al
1991; Wan and Swerdlow 1993; Wan et al 1994; Caine et al 1995; Ralph et
al 1999; Chapter 6), it was suggested that the DA characteristics in the APO-
SUS contribute to gating disturbances found in these rats. Therefore, it was
expected that APO-SUS rats would also show an AEP gating deficit. Because
the DA system of the APO-UNSUS and ACI rats is opposite to that of the APO-
SUS (Cools et al 1990, Chapter 4), the former two rat genotypes were
expected to show no deficits. The contribution of the DA activity in the dorsal
striatum to gating disturbances was assessed by studying gating in the
WAG/Rij rats, since these rats were suggested to posses a higher DA activity
in the dorsal striatum as compared to the APO-SUS (see Chapter 4), while
both rat genotypes have a high DA reactivity in the ventral striatum (Cools et
al 1990, Chapter 4). When besides a high DA reactivity in the mesolimbic
system, also a high DA activity in the dorsal striatum would play a role in PPI
and AEP gating, then WAG/Rij's were expected to show more deficits than the
APO-SUS rats.
In chapter 5, the results are presented of the study in which the
genotype effects on AEP gating and PPI were investigated. Significant AEP
gating of several components was observed at two cortical electrode
positions. Gating of the vertex N50 was significantly reduced in the WAG/Rij
rats as compared to in the remaining three rat genotypes (APO-SUS, APO-
UNSUS and ACI). The effects on the amplitude to S1 partially mediated these
effects. No differences were found in PPI between the ACI and WAG/Rij rats:
both showed normal PPI. However, basal startle reactivity was significantly
higher in ACI as compared to the WAG/Rij rats.
127

This study provides evidence for the relative role of dorsal and ventral
striatal DA on PPI and AEP gating. The PPI deficit in APO-SUS and not in the
other genotypes, suggests that a DA dominance of the ventral striatum
contributes to this deficit. Additionally, since WAG/Rij's posses a high DA
reactivity in the ventral striatum as well, but show normal PPI, it can be
suggested that these rats have a mechanism that protects them from PPI
deficits, possibly through their high DA activity in the dorsal striatum. Ventral
striatal regulation of PPI has been suggested to be mediated via the
GABAergic projection to the ventral pallidum that projects to the
pendunculopontine nucleus of the tegmentum (PPTg) (Braff and Geyer 1990;
Swerdlow et al 1990c; Kodsi and Swerdlow 1994; Kretschmer and Koch
1998).
In contrast, the N50 gating deficit in WAG/Rij's and not in the other
genotypes, suggests that a high DA activity in the dorsal striatum versus a
high DA reactivity in the ventral striatum is necessary for such a gating deficit
to occur. This suggests that the dorsal striatal brain area is also involved in
the DA modulation of AEP gating in rats and that a general DA hyperactivity
in striatal areas is important in this gating deficit. However, the effects on
N50 gating in WAG/Rij's were partially mediated by the effects on the
amplitude to S1, similar to what has been found with systemic injections of
amphetamine and intra-NAC quinpirole injections in rats (Adler et al 1986,
1988; Bickford-Wimer et al 1990; Stevens et al 1991; 1995, 1996; Johnson
et al 1998; Chapters 6-7). Also, in schizophrenic patients reductions in both
gating and amplitude to S1 have been reported (Adler et al 1982; Freedman
et al 1983, 1987; Boutros et al 1991; Judd et al 1992; Cullum et al 1993; Jin
et al 1997; Zouridakis et al 1997; Patterson et al 2000). Given these findings
that the response to S1 (CAMP) is reduced, whereas the response to S2
(TAMP) is not affected, it can be argued that merely the amplitude and not
the inhibitory process between S1 and S2 is affected by DA
neurotransmission.
The sequence of events as illustrated in Figure 8.4 can explain this
reduction in the amplitude to S1 and increase in TC ratio (reflecting a
reduction in gating). Jin and colleagues (Jin et al 1997; Patterson et al 2000)
have suggested that the reduction in the initial P50 response to S1 could to
be an important contributor to the decrease in gating in schizophrenic
patients. With single-trial analysis they have found that patients have higher
trial-to-trial latency variability (temporal variability or jitter) in S1 P50
responses than normal subjects, while the S2 showed the same variability as
in controls (Jin et al 1997). The authors have proposed that 'jitter' may
contribute to central inhibitory processes. They have suggested that this
'jitter' phenomenon could be linked to the concept of 'occlusion' described by
Adler et al (1982): "When a neuronal population is hyperactive, its constant
background discharge makes it less likely, that the majority of the neurons
will respond synchronously to the stimulus being studied". It has been argued
that this could consequently lead to smaller amplitudes and increased TC
ratios. The hyperactivity was proposed to be due to a lack of functional
inhibitory input.
Furthermore, Adler et al (1982) have suggested that the response to
S1 could not have fully activated inhibitory mechanisms, because the
response to S1 itself was already smaller in patients. DA has been proposed
to increase the responsiveness of neurons thereby making them hyperresponsive
to multiple afferents (or enhancing occlusion) (Cullum et al 1993;
Waldo et al 1994). Whether this is a good explanation for the DA modulation
of AEP gating in WAG/Rij's, could be further studied by using single-trial
128

analysis in order to investigate temporal variability. When this is indeed the
case, it would be expected that WAG/Rij's would have a higher temporal
variability in S1 responses as compared to the other rat genotypes.
Figure 8.4 Hypothesized sequence of events explaining the reduction
in both the amplitude to S1 and gating: the role of DA
S1
Lack of inhibitory input
Hyperactive neuronal population
Less likely that specific neurons will
respond synchronously to S1 (occlusion)
No full activation
inhibitory mechanisms
S2
High trial-to-trial latency variability
(temporal variability or jitter)
Smaller amplitude to S1 (CAMP)
Less reduction amplitude to S2 (TAMP)
Higher TC ratio (reduced gating)
From the results as reported in Chapter 5, it was concluded that both
gating processes are regulated differently by DA in the ventral and dorsal
striatum. So, this study provides additional evidence for the test specificity of
PPI and AEP gating. Several experiments were proposed to test the following
hypotheses. The first hypothesis is that the low DA activity in the dorsal
striatum and high DA reactivity in the ventral striatum in the APO-SUS
contribute to the PPI deficit in these rats. Then, PPI should be normalized
when APO-SUS rats are injected with a DA agonist in the dorsal striatum
and/or a DA antagonist in the ventral striatum. Also, PPI deficits should be
induced when APO-UNSUS and ACI rats are injected with a DA antagonist in
the dorsal striatum and a DA agonist in the ventral striatum. Finally,
WAG/Rij's should show reduced PPI when they are injected with a DA
antagonist in the dorsal striatum. The second hypothesis is that the high DA
activity in the dorsal striatum and high DA reactivity in the ventral striatum in
the WAG/Rij contribute to the N50 gating deficit in these rats. Then, AEP
gating should be normalized when WAG/Rij's are injected with a DA
antagonist in the dorsal striatum and/or a DA antagonist in the ventral
striatum. Furthermore, AEP gating deficits should be induced when APO-
UNSUS and ACI rats are injected with a DA agonist in the ventral striatum
and when APO-SUS rats are injected with a DA agonist in the dorsal striatum.
Main results and conclusions
129

Dopamine and information processing Chapter 5
� Gating of the vertex N50 was significantly reduced in the
WAG/Rij rats as compared to in the remaining three rat
genotypes (APO-SUS, APO-UNSUS and ACI). The effects on
the amplitude to S1 partially mediated these effects.
� No differences were found in PPI between the ACI and
WAG/Rij rats: both showed normal PPI. However, basal
startle reactivity was significantly higher in ACI as compared
to the WAG/Rij rats.
� This study provides evidence for the relative role of dorsal
and ventral striatal DA on PPI and AEP gating.
� The PPI deficit in APO-SUS and not in the other genotypes,
suggests that a DA dominance of the ventral striatum
contributes to this deficit.
� In contrast, the N50 gating deficit in WAG/Rij's and not in
the other genotypes, suggests that a high DA activity in the
dorsal striatum versus a high DA reactivity in the ventral
striatum is necessary for such a gating deficit to occur.
� Finally, it was concluded that the APO-SUS is a good model
for schizophrenia concerning PPI and latent inhibition
(Ellenbroek et al 1995), but not with respect to the AEP
gating deficit in schizophrenic patients.
8.2 STIMULATION
OF DOPAMINE D2 RECEPTORS IN THE NUCLEUS
ACCUMBENS AND THE EFFECTS ON INFORMATION PROCESSING
As we have mentioned in Chapters 1, 5 and 6, stimulation of DA D2 receptors
in the mesolimbic terminal region (e.g. NAC) has been shown to reduce PPI
(Swerdlow et al 1990b, 1992; Wan and Swerdlow 1993; Wan et al 1994).
Furthermore, the PPI disruption induced by intra-NAC microinjections of the
DA D2 agonist quinpirole (10 µg/0.5 µl) has been shown to be antagonized by
pretreatment with haloperidol (0.05-0.1 mg/kg, SC) (Wan and Swerdlow
1993). Finally, Wan et al (1994) have found a tendency for quinpirole to be
more effective in the core and central accumbens compared to the shell and
anteromedial accumbens. Also, injector distance from midline was positively
correlated with the PPI-disruptive effect of quinpirole (for the 10 µg /0.5 µl
dose). The VP-PPTg pathway has been suggested to be the relay for the
disruptive effects on PPI exerted by the NAC DA system (Braff and Geyer
1990; Swerdlow et al 1990c; Kodsi and Swerdlow 1994; Kretschmer and
Koch 1998).
130

It is not clear whether NAC DA D2 receptors are involved in the
DA modulation of AEP gating in rats. Amphetamine effects on
AEP gating were only partially antagonized by the D2 antagonist
sulpiride (Stevens et al 1991) and the D2 agonist 7-OH-DPAT
did not reduce AEP gating (Ellenbroek et al 1999). Therefore, we
have decided to study the involvement of DA D2 receptors in
AEP gating by injecting the DA agonist quinpirole (10 µg/0.5 µl)
bilaterally into the NAC in chapter 6. Furthermore, the possible
antagonistic effect of the DA D2 antagonist haloperidol (0.1
mg/kg, SC) was studied.
Considering that the NAC shell and core have been found to differ
anatomically as well as functionally as has been discussed in Chapter 1, it was
decided to separately analyze the effects of quinpirole on gating parameters
in both these NAC sites (Zahm and Brog 1992; Cools et al 1993, 1995;
Prinssen et al 1994; Koshikawa et al 1996; Groenewegen et al 1999a,b;
Zahm 1999).
The results in the present thesis (Chapter 6) have shown that
hippocampal gating was reduced only in the shell-injected rats, whereas
cortical gating was affected by quinpirole when injected in both NAC sites.
Pretreatment with haloperidol (0.1 mg/kg, SC) fully antagonized the
quinpirole effects on cortical gating, but did not affect the quinpirole-induced
reduction in hippocampal gating. As has already been mentioned in paragraph
8.1.2, gating reduction induced by DA activation seems to be mediated
predominantly by the effects on the amplitude to S1. We have presented a
model by which both reduced gating and CAMP could be explained based on
the findings of Jin and colleagues (see Figure 8.4).
In chapter 6, we have proposed the circuitry through which the
differential effects of shell and core quinpirole injections on hippocampal
versus cortical gating might be explained. There are no direct projections
from the NAC to the hippocampus or cortex, only indirect circuitry's. Indirect
effects of stimulation of DA receptors in striatal areas on the amplitude to S1
and TC ratio are further discussed here and a model is presented in Figures
8.5-8.9.
Quinpirole injections in the NAC shell decreased both gating and CAMP
as measured on the cortex and the hippocampus (Chapter 6). The NAC shell
has an indirect inhibitory projection to the VTA (Groenewegen et al 1999a,b)
via the ventral pallidum (VP) (for review see Heimer et al 1995). The VTA
provides DA inputs to the hippocampal dendate gyrus (DG) and cortical areas
such as the entorhinal cortex (EC) and medial prefrontal cortex (mPFC)
(Berger et al 1976; Swanson 1982; Björklund and Lindvall 1984; Fuxe et al
1985; Descarries et al 1987). Therefore, quinpirole injections in the NAC shell
could have induced a reduction in feedback inhibition via the VP (see pathway
in Figure 8.5). DA could locally increase the responsiveness of neurons
thereby making them hyper-responsive to multiple afferents (occlusion) that
could decrease synchrony in their response to the auditory input, which could
then lead to a decreased amplitude of the evoked potential to S1 (Cullum et
al 1993, Waldo et al 1994).
Figure
8.5
VTA
NAC
shell VP VT
DG, EC,
mPFC Hippocampal
and cortical
DA↑
GABA
↑ GABA ↓
DA↑
gating/CAMP ↓
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Furthermore, there might be an alternative explanation for the effects of
quinpirole in the NAC shell on cortical parameters. The VP that is innervated
by the NAC shell, also sends GABAergic fibers directly to the mPFC (for review
see Groenewegen et al 1993, 1999b; Heimer et al 1995). Additionally, the VP
projects to the cortex via the thalamus. Thus, it can be proposed that DA
activation in the NAC shell might lead to a reduction in GABAergic output to
the mPFC (see pathway in Figure 8.6) and disinhibition of TC cells (see
pathway in Figure 8.7) via the VP. This could have resulted in cortical neurons
to become hyper-responsive. Consequently this leads to occlusion and a
reduction in cortical CAMP.
VTA
Figure
8.6
DA↑
Figure
8.7
VTA
NAC
shell VP mPFC Cortical
gating/CAMP ↓
GABA ↑ GABA ↓
NAC
shell
VP
DA↑ GABA
↑ GABA ↓
TC Cortex
GLU ↑
Cortical
gating/CAMP ↓
Quinpirole injections in the NAC core decreased gating and CAMP as
measured on the cortex (Chapter 6). Core matrix neurons have been
suggested to send inhibitory projections to the substantia nigra pars reticulata
(SNr) (Groenewegen et al 1999a). The SNr sends GABAergic fibers to the
thalamus that, in turn, innervates the cortex. DA activity in the NAC core can
therefore be suggested to result in a disinhibition of TC neurons via the SNr
(see pathway in Figure 8.8). This could have induced the cortical neurons to
become hyper-responsive and this could consequently lead to occlusion and a
reduction in cortical CAMP.
Figure
8.8
SNc
DA↑
NAC
core
SNr
TC
GABA ↑ GABA ↓
GLU ↑
Cortex
Cortical
gating/CAMP ↓
In Chapter 5, we have found that WAG/Rij's that have a high DA activity in
the dorsal striatum and a high DA reactivity in the ventral striatum, have a
N50 gating deficit which was also partially explained by the reduction in N50
CAMP. APO-SUS with a low DA activity in the dorsal striatum and ACI and
APO-UNSUS with low DA reactivity in the ventral striatum did not show
deficits in N50 gating. The high DA activity in the dorsal striatum may
contribute to the N50 gating reduction in WAG/Rij's and the high DA reactivity
in the ventral striatum in the APO-SUS may not be a sufficient condition for
the N50 gating deficit to occur. The dorsal striatum provides inhibitory inputs
to the GABAergic neurons in the SNr (Chevalier et al 1985; Deniau and
Chevalier 1985) and subsequently nigrothalamic fibers are directed to the TC
neurons that send projections to the cortex. So, this means that enhancing
DA activity in the dorsal striatum (CPu) can result in a disinhibition of TC
neurons via the SNr (see pathway in Figure 8.9). This could induce cortical
neurons to become hyper-responsive and consequently lead to occlusion and
132

a reduction in cortical CAMP, similar to what has been described above for the
effects of DA activation in the NAC core.
Figure
8.9
SNc CPu SNr,GPi TC Cortex Cortical
DA ↑ GABA
↑ GABA ↓ GLU ↑ gating/CAMP ↓
According to above described hypotheses this could imply that general striatal
DA activation in the WAG/Rij's could have induced the N50 gating deficit via a
disinhibition of TC neurons.
Main results and conclusions
Stimulation DA D2 receptors in the NAC and AEP gating
Chapter 6
� Hippocampal gating was reduced only in the shell-injected
rats, whereas cortical gating was affected by quinpirole when
injected in both NAC sites.
� Pretreatment with haloperidol fully antagonized the
quinpirole effects on cortical gating, but did not affect the
quinpirole-induced reduction in hippocampal gating.
� Gating reduction induced by DA activation seems to be
mediated predominantly by the effects on the amplitude to
S1.
8.3 REDUCTION IN GLUTAMATE ACTIVITY BY KETAMINE AND THE
EFFECTS ON INFORMATION PROCESSING
Besides dopamine, also glutamate has been proposed to play a role in some
of the abnormalities in schizophrenia (Javitt 1987; Lathi et al 1995; Goff and
Wine 1997). The glutamate hypothesis of schizophrenia is based on the
observation of psychotomimetic effects of non-competitive N-methyl-Daspartate
(NMDA) receptor antagonists, such as phencyclidine (PCP),
dizocilpine (MK-801) and ketamine. Therefore, effects of these drugs have
been studied in animal models for information processing disturbances in
schizophrenic patients.
Systemic effects of non-competitive NMDA receptor antagonists have
reliably shown to decrease PPI (Geyer et al 1989; Mansbach 1991; Mansbach
and Geyer 1991; Hoffman et al 1993; Bakshi et al 1994; Johansson et al
1994; Wiley 1994). As described in Chapter 1, local effects in the amygdala
or dorsal hippocampus have been suggested to mediate systemic effects of
non-competitive NMDA antagonists on PPI (Bakshi and Geyer 1998). These
effects are probably not modulated by monoamines, since haloperidol did not
antagonize effects of PCP on PPI (Geyer et al 1989; Keith et al 1991). Adler et
al (1986) have shown that PCP interferes with the suppression of the cortical
N50 response to S2 in the AEP gating paradigm in rats. The by PCP-induced
reduction in AEP gating could be antagonized by haloperidol (Adler et al
1986). Further studies showed (Miller et al 1992) that selective lesioning of
133

the noradrenergic input with the neurotoxin DSP-4, as well as less selective
depletion of monoamines with reserpine, blocked the loss of hippocampal
gating induced by PCP and MK-801. The authors have suggested that drugs
such as PCP most likely disrupt gating by increasing monoaminergic activity.
Since PCP is also known as a DA reuptake inihibitor, the effects
of PCP could be explained in terms of DA effects. Therefore, it is
of interest to study the influence of a more specific NMDA
antagonistic drug such as ketamine in order to establish the
effects on both PPI and AEP gating (Chapter 7)
In this thesis (Chapter 7), we have presented a study in which we have
investigated the effects of the non-competitive NMDA receptor antagonist
ketamine on both PPI and AEP gating. Ketamine disrupted PPI of the startle
response and even induced prepulse facilitation. Second, the same dose of
ketamine that reduced PPI did not affect sensory gating in the AEP gating
paradigm. In contrast, d-amphetamine diminished gating of two of the
components of the AEP (the N35 and P61). We have argued that the
discrepancy between our results with ketamine and the results of Adler et al
(1986) with PCP could be due to the difference in drugs that were
administered in both studies. PCP is also known to act as a DA reuptake
inhibitor, thereby enhancing the DA activity (Johnson et al 1984; Gerhardt et
al 1987; Koek et al 1989; Akunne et al 1991), whereas Akunne et al (1991)
have demonstrated that ketamine has more selective NMDA antagonistic
properties than PCP. This suggestion is corroborated by the finding that the
PCP-induced disruption of AEP gating was antagonized by haloperidol (Adler
et al 1986).
However, at the time we have used different electrode placements
(FP/S) than Adler et al (1986, vertex). Therefore, it is imperative to also
study effects of ketamine and other non-competitive NMDA receptor
antagonists on the vertex components in future studies. Although we have
administered d-amphetamine to validate the animal model for disturbances in
AEP gating and indeed a disruption in gating of the N35 and P61 components
was found, this difference in electrode position could be a limitation of the
study as presented in Chapter 7.
In this experiment another important effect was found, namely the
significant test sequence effect for the ketamine-induced decrease in PPI.
Effects of ketamine on PPI were stronger in naive animals than in non-naive
animals. In naive animals, a large decrease of PPI and even prepulse
facilitation was found. In non-naive animals, a small and non-significant effect
of ketamine was found. It was suggested that the animals could have been
less sensitive to the second administration of ketamine in the PPI experiment.
These results suggest that it could be important to use a between-group
design to study drug effects in the PPI and AEP gating paradigms, instead of
testing the effects of drugs on both types of gating in the same session
and/or in the same animals.
134

Main results and conclusions
Ketamine effect on PPI and AEP gating Chapter 7
� Ketamine disrupted PPI of the startle response and even
induced prepulse facilitation.
� The same dose of ketamine that reduced PPI did not affect
AEP gating.
� The differential effects of ketamine on PPI and AEP gating
provide additional evidence for the test specificity of both
paradigms.
8.4 TEST SPECIFICITY OF AEP GATING AND PREPULSE INHIBITION
The second important aim of the present thesis was to determine to what
extent the AEP gating and PPI paradigms represent similar or different
aspects of information processing. Similarities and differences between both
paradigms have already been discussed in Chapter 1. It was concluded that
PPI and AEP gating have neural substrates that show overlap on certain parts,
but also differ on other parts of the neural substrate. These similarities and
differences are summarized in Tables 8.2 and 8.3. In this thesis, we have
presented some additional evidence for these considerations that are also
incorporated in this section.
Stimulation of DA D2 receptors has been found to affect both PPI
(Swerdlow et al 1990, 1992; Wan and Swerdlow 1993; Wan et al 1994) and
AEP gating (Chapter 6) in rats (see Table 8.2). Several differences were found
between AEP gating and PPI (see Table 8.3). First, PPI is reduced at an ISI of
500 ms as compared to an ISI of 100 ms in rats (Ellenbroek et al 1999). In
contrast, significant gating was found for several AEP gating components at
the 200 to 600 ms ISIs and no differences were found in gating between
these ISIs (Chapter 2). Secondly, APO-SUS rats show deficits in PPI and not
in N50 gating, whereas WAG/Rij's have N50 gating disturbances without
deficits in PPI (Chapter 5). Both these genotypes differ in their DA system.
This suggests that both information processing paradigms have different
underlying neural substrates. Third, PPI has been found to be disrupted by
systemic injections with ketamine (10 mg/kg). The same dose of ketamine
did not decrease AEP gating in rats (Chapter 7).
135

Table 8.2 Similarities AEP gating and PPI
Similarities
� Long-lasting inhibitory processes in the auditory pathway
� Gating deficits in schizophrenic patients (1)
� Dependent on genetic factors: also asymptomatic family members (2)
� Trait deficit or biological marker for schizophrenia spectrum disorders:
also subjects with schizotypical personality disorder (3)
� No improvement with typical antipsychotics (haloperidol), normalized
with the atypical antipsychotic clozapine (4)
� Disturbance by DA agonists and non-competitive NMDA antagonists (5)
� Nicotinergic agents temporarily restore PPI and AEP gating deficits (6)
� Septo-hippocampal system (7) and nucleus accumbens DA D2
receptors (CH 6)
CH=Chapter (REFERENCES 1= Braff et al 1978, 1992; Adler et al 1982; 2= Waldo et al 1988, 1995;
Cadenhead et al 1999, 3= Cadenhead 1993, 1999, 2000; 4= Freedman et al 1983; Adler et al 1990;
Nagamoto 1996, 1999; Kumari et al 1999; Light et al 2000; 5= Mansbach et al 1988; Swerdlow et al
1996; Adler et al 1986; Bickford-Wimer et al 1990; Stevens et al 1995; Geyer et al 1989; Mansbach
et al 1991; Mansbach and Geyer 1991; Adler et al 1986; Miller et al 1992; 6= Kumari et al 1996;
Stevens et al 1997; Stevens and Wear 1997; 7= Caine et al 1992; Koch 1996; Bickford-Wimer et al
1990; Miller and Freedman 1995; Stevens et al 1998).
Table 8.3 Differences between AEP gating and PPI
Differences PPI AEP gating
� Output parameter � Reflex � EEG/AEP
� Stimuli � Prepulse-startle � Identical
� Maximal inhibition healthy
subjects
� ISI: 100-120 ms,
reduced at 500 ms
(1)
� ISI: 500 ms,
reduced 1000 ms (2)
� ISI: 150, 500 ms
and not at 75 ms (4)
� Deficit schizophrenic patients � ISI: 100-120 ms
(3*)
� DA D2/D3 agonist 7-OH-
DPAT
� Reduction (5) � No effect (6)
� PCP-induced reduction and
haloperidol pretreatment
� Not antagonized (7) � Antagonized (8)
� 5-HT2 receptor agonist DOI � Decrease (9) � Increase (10)
� Apomorphine in neonatal DA � Differentiation (11) � No differentiation
lesioned versus sham
lesioned rats
(12)
No correlation (humans and
rats) (6, 13)
� �
� Rats: Interstimulus interval � 500

8.5 THE HUMAN P50 AND THE RAT HOMOLOGUE IN AEP GATING?
In the introduction (Chapter 1) and Chapter 2, we have mentioned that it is
still not clear what the equivalent is for the human P50 in the rat. Some
propose an early vertex component (the P13) (Miyazato et al 1995, 1996,
1999a,b, 2000; Reese 1995a,b), whereas others suggest that the vertex N40-
N50 is the equivalent (Adler et al 1986, 1998; Boutros et al 1994, 1997a,b).
Several arguments have been presented that are in favor of the N40-N50
(that is thought to be modulated by the hippocampus) being the rat
homologue of the human P50 (see Table 8.4). In contrast, other arguments
have been presented by Miyazato and colleagues that suggest that the rat
P13 (that is thought to be modulated by the pendunculopontine nucleus of
the tegmentum, PPTg) and not the N40-N50 is the equivalent of the human
P50 (see Table 8.4). Especially the drug-induced changes by amphetamine,
cocaine and nicotine of N40-N50 gating are strong argument in favor of this
component, since such findings have not been reported for the rat P13.
However, the slow wave sleep (SWS)-induced effects on the P13 and not on
the N40-N50 and the shorter latency of the P13 are important arguments
against the N40-N50 and in favor of the P13.
Considering these limitations, more research should be focussed on
comparing properties of the human P50 and of rat midlatency AEP
components. It is of particular importance to investigate which of the above
mentioned rat AEP components respond in a similar fashion to certain
experimental manipulations such as varying the interstimulus interval (ISI)
and repetitive stimulation. The lack of standardized methods in the AEP
gating research is one of the remaining problems. Depending on which
component the authors are interested in, completely different recording
settings have been used. Future comparative AEP gating research should use
standardizing methods to allow comparison between data from various
laboratories. Until agreement is reached and sufficient experimental evidence
has been provided regarding the rat homologue for the human P50, it is
better to report data on multiple AEP components instead of focussing on just
one perhaps arbitrary component.
The amount of P50 gating in humans has been found to be
dependent on repetitive stimulation and the interstimulus
interval (ISI) (respectively, Starr et al 1997; Boutros and Belger
1999 and Adler et al 1982; Freedman et al 1983). In Chapter
2, we therefore present the study in which we have determined
the effects of repetitive stimulation (Experiment 1) and various
ISIs (Experiment 2) on rat AEP components.
The results suggest that gating is not limited to a restricted cortical
area or a single midlatency component. Gating was found for the vertex P17,
N22, N50 and FP/S P13, N35, P61. Gating was not significant for the vertex
N14 and P30 components. The same results were obtained with respect to
gating of these components in Chapter 5. Furthermore, repetitive stimulation
and ISI affected gating of several rat AEP components in a similar fashion as
has been shown for the human P50. Components such as the vertex P17 and
N22 showed a decrease in gating within several S1-S2 presentations, mainly
due to a decrease in amplitude to S1 (Experiment 1). Gating for most
components (such as the P17, N22, N50 and FP/S N35, P61) was ISI
137

dependent (Experiment 2), but there was no interval in the 200 to 600 ms
range at which optimal gating occurred. The ISI effects on gating of the
vertex components were due to an increase of the amplitude to S2.
Table 8.4 Arguments in favor of the N40-N50 and P13 being P50
homologues
N40-N50 P13
� Both the rat N40-N50 and the human P50 are
midlatency EPs that demonstrate filtering to
paired auditory stimuli separated by 500 msec
(1).
� Like the human P50, the rat N40-N50 shows
recovery of the response to S2 when the ISI
between S1 and S2 is prolonged (2).
� Rat N40-N50 gating is sensitive to stimulus
change which has also been shown for the
human P50, when utilizing non-identical pairs in
the AEP gating paradigm (3).
� Rat N40-N50 gating has been shown to be
sensitive to pharmacological manipulation with
amphetamine which has recently also been
reported for the human P50 (4).
� Amphetamine-induced disturbances in rat N40-
N50 gating have been shown to be normalized
by nicotine due to a reduction in the amplitude
to S2. Nicotine (either by smoking or chewing
nicotine gum) also produced normalization of
P50 gating in both schizophrenic patients and
normal non-gating individuals by reducing the
testing amplitude (5).
� Cocaine abusers have reduced auditory P50
amplitude and suppression compared to normal
controls. A similar effect of cocaine has been
described for the rat N40-N50 (6).
� The human P50 and
rat P13 have been
shown to be
diminished during slow
wave sleep (SWS) and
reappear with waking
amplitudes during REM
sleep. In contrast, the
N40-N50 is present
during waking and
SWS and reduced
during REM sleep (7).
� Attenuation of
response at stimulus
rates exceeding 1 Hz
has been reported for
the human P50 and
rat P13 (8).
� The P13 has the
same polarity as the
human P50 and has a
shorter latency. In
contrast, the rat N40
is a negative
component with a long
latency in a species
with a small brain (9).
CH=Chapter (REFERENCES 1= Adler et al 1982, 1986; 2= Adler et al 1982, 1986; Freedman et al
1983; Zouridakis and Boutros 1992; 3= Guterman et al 1992; Boutros et al 1997a; 4= Adler et al
1986, 1988; Stevens et al 1991, 1995, 1996; Johnson et al 1998; Light et al 1999; 5= Adler et al
1990, 1992; Stevens et al 1995; 6= Fein et al 1996; Boutros et al 1994, 1997b; 7= Erwin and
Buchwald 1986a; Miyazato et al 1995, 1999a; 8= Erwin and Buchwald 1986b; Miyazato et al 1995;
9= Miyazato et al 1999a)
The findings that the vertex N14 and P30 showed no gating and that
the FP/S P13 was not ISI dependent suggests that these components are
unlikely homologues for the human P50. Also, results in Chapter 7 show that
gating of the FP/S P13 was not affected by amphetamine which underlines
this suggestion. The findings that gating of the vertex P17 and N22
components was decreased with repetitive stimulation and was ISI
dependent, makes these components the most likely candidates for the rat
homologue of the human P50. Also, since both rat components had a shorter
latency than 50 msec and because of the smaller brains in rats, these
components are more likely candidates. Although the vertex N50 showed
significant gating that was ISI dependent, N50 gating did not decrease with
repetitive stimulation. Furthermore, it can be argued that a smaller latency is
138

more probable and therefore a rat N50 as compared to the human P50 might
be an argument against this rat component being the equivalent. However,
like the human P50 (Light et al 1999), this components has been shown to be
dependent on DA manipulation (Adler et al 1986, 1988; Stevens et al 1991,
1995, 1996; Johnson et al 1998; Chapter 6). Finally, although gating of the
FP/S N35 was not reduced with repetitive stimulation, it is the most likely
FP/S equivalent because of two reasons. First, this component showed
significant gating that was ISI dependent (Chapter 2). Secondly, N35 gating
could be reduced by amphetamine (Chapter 7).
An important consideration is, however that similar ISI and repetitive
stimulation effects have also been mentioned for the human N100 component
(Davis et al 1966; Fruhstorfer et al 1970). Although these findings for the
N100 could be dependent on the properties of the preceding P50, this could
mean that specific rat AEP components showing above-mentioned
characteristics might actually correspond to either the human P50 or N100. Of
interest is the recent preliminary report by Boutros et al (1999). They have
found that schizophrenic patients have difficulty in 'gating out' irrelevant input
and 'gating in' relevant input at the early pre-attentive stage (P50), but also
at the later early-attentive stage (N100). Furthermore, they also discuss the
earlier data found by Waldo et al (1988). Waldo et al (1988) have studied two
defects in schizophrenic patients and their relatives. They have found that
both P50 gating and a reduction in the amplitude of the N100 wave (which
has been related to a failure to attend to particular features of interest in a
stimulus) occur together in schizophrenics (even in very good prognosis,
mildly ill subjects). In contrast, the defect in the gating of P50 occurs in half
of the relatives, whereas N100 amplitudes are not diminished. Both Waldo et
al (1988) and Boutros et al (1999) have interpreted these results as follows:
"relatives with the P50 gating defect can compensate for that defect at a
subsequent stage of information processing, as demonstrated by their large
amplitude N100 wave, whereas schizophrenic patients cannot".
More comparative studies are necessary to establish which of the rat
AEP components can be considered as the rat homologue for the human P50.
Since the human P50 has been found to be sensitive to stimulus change
(Guterman et al 1992), we have done a study using non-identical pairs to
investigate which rat AEP components are similarly affected by this particular
experimental manipulation as the human P50. Data from this study have not
been presented in this thesis. However, we are currently in progress
analyzing the data.
Main results and conclusions
Effects of repetitive simulation and the interstimulus interval on
AEP gating Chapter 2
� Gating is not limited to a restricted cortical area or a single
midlatency component.
� The findings that the vertex N14 and P30 showed no gating
and that the FP/S P13 was not ISI dependent suggests that
these components are unlikely homologues for the human
P50. Also, results in Chapter 7 show that gating of the FP/S
P13 was not affected by amphetamine which underlines this
suggestion.
139

� The findings that gating of the vertex P17 and N22
components was decreased with repetitive stimulation and
was ISI dependent, makes these components the most likely
candidates for the rat homologue of the human P50. Also,
since both rat components had a shorter latency than 50
msec and because of the smaller brains in rats, these
components are more likely candidates.
� Although the vertex N50 showed significant gating that was
ISI dependent, N50 gating did not decrease with repetitive
stimulation. Furthermore, it can be argued that a smaller
latency is more probable and therefore a rat N50 as
compared to the human P50 might be an argument against
this rat component being the equivalent. However, like the
human P50 (Light et al 1999), this components has been
shown to be dependent on DA manipulation (Adler et al
1986, 1988; Stevens et al 1991, 1995, 1996; Johnson et al
1998; Chapter 6).
� Finally, although gating of the FP/S N35 was not reduced
with repetitive stimulation, it is the most likely FP/S
equivalent because of two reasons. First, this component
showed significant gating that was ISI dependent (Chapter
2). Secondly, N35 gating could be reduced by amphetamine
(Chapter 7).
� An important consideration is, however that similar ISI and
repetitive stimulation effects have also been mentioned for
the human N100 component (Davis et al 1966; Fruhstorfer
et al 1970).
� Future comparative AEP gating research should use
standardizing methods to allow comparison between data
from various laboratories.
8.6
IMPLICATIONS FOR FUTURE RESEARCH ON ANIMAL MODELS FOR
DISTURBANCES IN AEP GATING AND PREPULSE INHIBITION
In this thesis, evidence was provided for a differential role of the DA
subsystems in PPI and AEP gating. A DA dominance of the mesolimbic system
was proposed to be of importance in PPI, whereas a general striatal DA
hyperactivity was suggested to modulate AEP gating. However, DA
modulation of AEP gating was shown to be mediated predominantly through
its effects on the amplitude to S1. Several hypothetical pathways were
presented via which these DA effects could influence AEP gating and the
amplitude to S1. Further studies on the striatal circuitry's remain to be done
in order to elucidate the mechanisms underlying these effects. Single-trial
analyses can be a useful approach in these studies. DA -induced reduction in
the amplitude to S1 could be caused by an increase in responsiveness of
neurons thereby making them hyper-responsive to multiple afferents which
could lead to temporal variability and consequently to smaller amplitudes.
Since this has been suggested for both the DA effects in rats and also in
140

schizophrenic patients, this could be an interesting approach for comparative
AEP gating research.
We have presented a review of the similarities and differences between
the AEP
gating and PPI paradigms. Furthermore, we have provided some
additional evidence for the test specificity of both gating measures. So, it can
be concluded that both paradigms could separately provide valuable
information concerning disturbances in gating mechanisms implicated in
schizophrenia. Especially since the atypical antipsychotic clozapine has
recently been shown to normalize both gating measures in patients, both
paradigms can be considered as interesting models for preclinical research on
new antipsychotic drugs.
8.7 REFERENCES
Abduljawad
KA, Langley RW, Bradshaw CM, Szabadi E (1999) Effects of bromocriptine and haloperidol
on prepulse inhibition: comparison of the acoustic startle eyeblink response and the N1/P2 auditoryevoked
response in man. J Psychopharmacol 13:3-9
A dler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R (1982) Neurophysiological
evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol
Psychiatry 17:639-654
Adler LE, Rose G, Freedman
R (1986) Neurophysiological studies of sensory gating in rats: effects of
amphetamine, phencyclidine, and haloperidol. Biol Psychiatry 21: 787–798
Adler LE, Pang K, Gerhardt G, Rose GM (1988) Modulation of the gating of auditory
evoked potentials
by norepinephrine: pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry
24:179-190
Adler LE, Gerhardt
GA, Franks R, Baker N, Nagamoto H, Drebing C, Freedman R (1990) Sensory
physiology and catecholamines in schizophrenia and mania. Psychiatry Res 31:297-309
Adler LE, Hoffer LH, Griffith J, Waldo M, Freedman R (1992) Normalization of deficient sensory
gating
in the relatives of schizophrenics by nicotine. Biol Psychiatry 32:607-616
Adler LE, Hope C, Hoffner LD, Stephen C, Young D, Herhardt G (1994) Bromocriptine
impairs P50
auditory sensory gating in normal control subjects. Biol Psychiatry 35:630
Adler LE, Olincy A, Waldo M, Harris JG, Griffith JG, Stevens K, Flach K, Nagamoto
H, Bickford P,
Leonard S, Freedman R (1998) Schizophrenia, sensory gating and nicotine receptors. Schizophr Bull
24:189-202.
Ak unne HC, Reid AA, Thurkauf A, Jacobson AE, de Costa BR, Rice KC, Heynes MP, Rothman RB (1991)
[3 H)1-[2-(2-Thienyl) cyclohexyl piperidine labels two high affinity binding sites in human cortex:
further evidence for phencyclidine binding sites associated with the biogenic amine reuptake
complex. Synapse 8:289–300
Avakyan RM, Arushanyan EB (1976)
Effects of catecholaminergic drugs on epileptogenic properties of
the caudate nucleus. Neurosc Behav Physiol 7:13-16
Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes
phencyclidine-induced deficits in
sensorimotor gating of the startle response. J Pharmacol Exp Ther 271: 787–794
Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption of prepulse
inhibition
produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394-8401
Berger B, Thierry AM, Tassin JP, Moyne MA (1976) Dopaminergic innervation of the rat prefrontal
cortex: a fluorescence histochemical study. Brain Res 106:133-145
Björklund A, Lindvall O (1984) Dopamine-containing system in the CNS.
In: Björklund A, Hökfelt O
(Eds) Classical transmitters in the CNS, Part I (Handbook of chemical neuroanatomy). Elsevier,
Amsterdam, pp 55-122
Boutros N, Zouridakis G, Overall
(1991) Replication and extension of the P50 findings of the P50
findings in schizophrenia. Clin Electroencephalogr 22:40-45
Bo utros NN, Uretsky N, Berntson G, Bornstein R (1994) Effects of cocaine on sensory inhibition in rat:
preliminary data. Biol Psychiatry 36:242-248
Boutros NN, Bonnet KA, Millana R, Liu J (1997a)
A parametric study of the N40 auditory evoked
potential. Biol Psychiatry 42:1051-1059
Boutros NN, Uretsky N, Liu J (1997b) Effects
of repeated cocaine on sensory inhibition in rat:
preliminary data. Biol Psychiatry 41:462-466
Boutros NN, Belger A (1999) Midlatency evoked
potentials attenuation and augmentation reflect
different aspects of sensory gating. Biol Psychiatry 45:917-922
Boutros NN, Belger A, Campbell D, D'Souza CD, Krystal J (1999). Comparison
of four components of
sensory gating in schizophrenia and normal subjects: a preliminary report. Psychiatry Res 88:199-
130
Bickford-Wimer PC, Nagamoto H, Johnson R, Adler LE, Egan M, Rose GM, Freedman R (1990) Auditory
sensory gating in hippocampal neurons: a model system in the rat. Biol Psychiatry 27:174-192
Braff DL, Stone C, Callaway E, Geyer MA, Glick ID, Bali L (1978) Prestimulus effects on human startle
reflex in normals and schizophrenics. Psychophysiology 14:339–343
141

Braff DL, Grillon C, Geyer MA (1992) Sensorimotor gating and schizophrenia: human and animal
model studies. Arch Gen Psychiatry 47:181–188
Buzsáki G, Smith A, Berger S, Fisher LJ, Gage FH (1990a) Petit mal epilepsy and Parkinsonian tremor:
hypothesis of a common pacemaker. Neuroscience 36:1-14
Buzsáki G, Laszlovszky I, Lajtha A, Vadása C (1990b) Spike-and-wave neocortical patterns in rats:
genetic and aminergic control. Neuroscience 38:323-333
Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle prepulse inhibition and habituation in
patients with schizotypal personality disorder. Am J Psychiatry
150:1862-1867.
Cadenhead KS, Swerdlow NR, Shafer K, Diaz M, Braff DL (1999) Modulation of the startle response
and laterality in schizophrenic patients, their relatives and schizotypical personality
disorder:
evidence of inhibitory deficits. Proc Am Acad Neuropsychopharmacology 136.
Cadenhead
KS, Light GA, Geyer MA, Braff DL (2000). Sensory gating deficits assessed by the P50
event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry
157:55-59
Caine SB, Geyer MA, Swerdlow NS (1992) Hippocampal modulation of acoustic startle response and
prepulse inhibition in the rat. Pharmacol Biochem Behav 43:1201–1208
Caine SB, Geyer MA, Swerdlow NR (1995) Effects of D3/D2 dopamine receptor agonists and
antagonists on PPI of acoustic startle in the rat. Neuropsychopharmacology
12:139-145
Chevalier G, Vacher S, Deniau JM, Desban M (1985). Disinhibition as a basic process in the expression
of striatal function I: The striatonigral influence on tecto-spinal/tecto-diencephalic neurons.
Brain
Res 334: 215–226
Coenen
AM, Drinkenburg WH, Peeters BW, Vossen JM, Van Luijtelaar EL (1991). Absence epilepsy and
the level of vigilance in rats of the WAG/Rij strain. Neurosci Biobehav Rev 15: 259-263.
Cools AR, Brachten R, Heeren D, Willemen A, Ellenbroek B (1990) Search after neurobiological profile
of individual-specific features of Wistar rats. Brain Res Bull 24:49-69
Cools AR, Peeters BW (1992) Differences in spike-wave discharges in two rat selection lines
characterized by opposite dopaminergic activities. Neurosci Lett 134:253-256
Cools AR, de Beltran KK, Prinssen EPM, Koshikawa N (1993) Differential role of core and shell of the
nucleus accumbens in jaw movements of rats. Neurosc Res Comm 14:55-61
Cools AR, Miwa Y, Koshikawa N (1995) Role of dopamine D1 and D2 receptors in the nucleus
accumbens in jaw movements of rats: a critical role of the shell. Eur J Pharmacology
286:41-47
Cools AR, Ellenbroek BA, Gingras MA, Engbersen A, Heeren D (1997). Differences in vulnerability and
susceptibility to dexamphetamine in Nijmegen high and low responders to novelty: a dose-effect
analysis of spatio-temporal programming of behaviour. Psychopharmacology 132:181–187
Cullum
CM, Harris JG, Waldo MC, Smernoff E, Madison A, Nagamoto HT, Griffith J, Adler LE and
Freedman R (1993) Neurophysiological and neuropsychological evidence for attentional dysfunction
in schizophrenia. Schizophr Res 10:131-141
Danober
L, Deransart C, Depaulis A, Vergnes M, Marescaux C (1998) Pathophysiological mechanisms
of genetic absence epilepsy in the rat. Prog Neurobiol
55:27-57
Davis H, Mast T, Yoshie N, Zerlin S (1966) The slow response of the human cortex to auditory stimuli:
recovery process. Electroenceph Clin Neurophysiol 21: 105-113
Deniau JM, Chevalier G (1985) Disinhibition as a basic process in the expression of striatal functions
II: The striato-nigral influence on thalamocortical cells of the ventromedial
thalamic nucleus. Brain
Res 334:227–233
Depaulis
A, Vergnes M, Marescaux C, Lannes B, Warter JM (1988) Evidence that activation of GABA
receptors in the substantia
nigra suppresses spontaneous spike-and-wave discharges in the rat.
Brain Res 488:20-29
Deransart
C, Riban V, Lê BT, Marescaux C, Depaulis A (1999) Evidence for the involvement of the
pallidum in the modulation
of seizures in a genetic model of absence epilepsy. Neurosc Lett
265:131-134
Deransart
C, Riban V, Lê BT, Marescaux C, Depaulis A (2000) Dopamine in the striatum modulates
seizures in a generatic
model of absence epilepsy in the rat. Neuroscience 100:335-344
Descarries TW, Lemay B, Doucet G, Berger B (1987) Regional and laminar density of the dopamine
innervation in adult rat cerebral cortex. Neuroscience 21:807-824
Ellenbroek BA, Geyer MA, Cools AR (1995) The behavior of APO-SUS rats in animal models with
construct validity for schizophrenia. J Neurosci 15: 7604–7611
Ellenbroek BA, van Luijtelaar G, Frenken M, Cools AR (1999) Sensory gating in rats: lack of correlation
between auditory evoked potential gating and PPI. Schizophr Bull
25:777-788
Ellenbroek BA, Sluyter F, Cools AR (2000) The role of genetic and early environmental factors in
determining apomorphine susceptibility. Psychopharmacology 148:124-131
Erwin RJ, Buchwald JS (1986a) Midlatency evoked responses: Differential effects of sleep in the
human. Electroenceph Clin Neurophysiol 65:383-392
Erwin RJ, Buchwald JS (1986b) Midlatency evoked responses: Differential recovery cycle
characteristics. Electroenceph Clin Neurophysiol 64:417-423
Fein G, Biggens C, Mackay S (1996) Cocaine abusers have reduced auditory P50 amplitude and
suppression compared to both normal controls and alcoholics. Biol Psychiatry 39: 955-965
Freedman R, Adler LE, Waldo MC, Pachtman E, Franks RD (1983) Neurophysiological evidence for a
defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients.
Biol
Psychiatry 18:537-551
Freedman
R, Adler LE , Gerhardt GA, Waldo M, Baker N, rose GM, Drebing C, Nagamoto H, Bickford-
Wimer P and Franks R (1987) Neurobiological studies of sensory gating in schizophrenia. Schizophr
Bull 13:669-678
142

Fruhstorfer H, Soveri P, Järviletho T (1970) Short-term habituation of the auditory evoked response in
man. Electroenceph Clin Neurophysiol 28:153-161
Fuxe K, Agnati LF, Kalia
M, Goldstein M, Andersson K, Härfstrand A (1985) Dopaminergic system in
the brain and pituitary. In: Fluckiger E, Muller EE, Thorner MO (Eds) The dopaminergic system
(Basic and clinical aspects of neuroscience). Springer-Verlag,
Berlin, pp 11-25
Gerhardt GA, Pang K, Rose GM (1987) In vivo electrochemical demonstration of the presynaptic
actions of phencyclidine in rat caudate nucleus. J Pharmacol Exp Ther 241:714–721
Geyer MA, Braff DL, Mansbach RS (1989) Failure of haloperidol to block the disruption
of sensory
motor gating induced by phencyclidine and MK801. Biol Psychiatry 25:169A–170A
G off DC, Wine L (1997) Glutamate in schizophrenia: clinical and research implications.
Schizophr Res
27:157–168
Graham FK, Murray GM (1977) Discordant effects of weak prestimulation on magnitude
and latency of
the blink reflex. Physiol Psychol 5:108-114
Groenewegen HJ,
Berendse HW, Haber SN (1993) Organization of the output of the ventral pallidal
system in the rat: ventral pallidal efferents. Neuroscience 57:113-142
Groenewegen HJ, Galis de Graaf Y, Smeets WJ
(1999a) Integration and segregation of limbic corticostriatal
loops at the thalamic level: an experimental tracing study in rats. J Chem Neuroanatomy
16:167-185
Groenewegen HJ, Wright CI, Beijer AV, Voorn P (1999b) Convergence and segregation of ventral
striatal inputs and outputs. Ann NY Acad Sci 877:49-63
Guterman Y, Josiassen
RC, Bashor TR Jr (1992) Attentional influence on the P50 component of the
auditory event-related brain potential. Int J Psychophysiol 12:197-209
Heimer L, Zahm DS, Alheid GF (1995) Basal ganglia. In: Paxinos G (Eds) The rat nervous system.
Academic Press, San Diego.
Hoffman HS, Searle JL (1968) Acoustic and temporal factors in the avocation
of startle. J Acoust Soc
Am 43:269-282
Hoffman DC, Donovan H, Cassela
JV (1993) The effects of haloperidol and clozapine on the disruption
of sensorimotor gating induced by the non-competitive glutamate antagonist MK-801.
Psychopharmacology
111:339–344
Hutchison KE, Swift R (1999) Effect of d-amphetamine on PPI of the startle reflex in humans.
Psychopharmacology 143:394-400
Inoue M, Peeters B, Van Luijtelaar E, Vossen
J, Coenen A (1990) Spontaneous occurrence of spikewave
discharges in five inbred strains of rats. Physiol Behav 48:199-201
Inoue M, Ates N, Vossen JMH, Coenen
AML (1994) Effects of the neuroleptanalgesic Fentanyl-
Fluanisone (Hypnorm) on spike-wave discharges in epileptic rats. Pharmacol Biochem Behav 48:
547-551
Javitt CD (1987) Negative schizophrenic symptomatology and the PCP (phencyclidine) model of
schizophrenia. Hillside J Clin Psychiatry 9:12–35
Jin Y, Potkin
SG, Patterson JV, Sandman CA, Hetrick WP, Bunney WE Jr (1997) Effects of P50
temporal variability on sensory gating in schizophrenia. Psychiatry Res 70:71-81
Johansson C, Jackson DM, Svensson L (1994) The atypical
antipsychotic, remoxipride, blocks
phencyclidine-induced disruption of prepulse inhibition in the rat. Psychopharmacology 116:37–442
Johnson SW, Haroldson PE, Hoffer BJ, Freedman R (1984) Presynaptic dopaminergic
activity of
phencyclidine in rat caudate. J Pharmacol Exp Ther 229:321–332
Jo hnson RG, Stevens KE, Rose GM (1998) 5-Hydroxytryptamine2 receptors modulate auditory filtering
in the rat. J Pharmacol Exp Ther 285:643-650
Ju dd LL, McAdams L, Budnick N and Braff (1992) Sensory gating deficits in schizophrenia: new
results. Am J Psychiatry 149:488-493
Ke ith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine
and dizocilpine on prepulse inhibition of startle. Biol Psychiatry 30:557–566
Koch M (1996) The septo-hippocampal system
is involved in prepulse inhibition of the acoustic startle
response in rats. Behav Neurosci 110:468–493
Kodsi MH, Swerdlow NR (1995) Propels inhibition in the rat is regulated by ventral
and caudodorsal
striato-pallidal circuitry. Behav Neuroscience 109:912-928
Koek W, Colpaert FC, Woods JH, Kamenka JM (1989)
The phencyclidine (PCP) analog N-[1- (2-benzo
(B) thiophenyl) cyclohexyl] piperidine shares cocaine-like but not other characteristic behavioral
effects with PCP, ketamine and MK-801. J Pharmacol Exp Ther
250:1019–1027
Koshikawa N, Yoshida Y, Kitamura M, Saigusa T, Kobayashi M, Cools AR (1996) Stimulation of
acetylcholine or dopamine receptors in the nucleus accumbens differentially alters dopamine release
in the striatum of freely moving rats. Eur J Pharmacol 303:13-19
Kretschmer BD, Koch M (1998) The ventral pallidum mediates disruption of PPI of the acoustic startle
response induced by DA agonists, but not by NMDA antagonists. Brain Res 798:204-210
Kumari V, Checkley SA, Gray JA (1996) Effect of cigarette smoking on
PPI of the acoustic startle reflex
in healthy male smokers. Psychopharmacology 128:54-60
Kumari V, Soni W, Sharma T (1999) Normalization of information processing deficits in schizophrenia
with clozapine. Am J Psychiatry 156:1046-1051
Lathi AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanaesthetic
doses of ketamine stimulate
psychosis in schizophrenia. Neuropsychopharmacology 13:9–19
Light GA, Malaspina D, Geyer MA, Luber BM, Coleman
EA, Sackeim HA, Braff DL (1999) Amphetamine
disrupts P50 suppression in normal subjects. Biol Psychiatry 46:990-996
143

Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL (2000) Normal P50 suppression in
schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 157:767-
771.
Mansbach
RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in
the rat.
Psychopharmacology 94:507–514
Mansbach RS (1991) Effects of NMDA receptor ligands on sensorimotor gating in the rat. Eur J
Pharmacol 202:61–66
Mansbach RS, Geyer MA (1991) Parametric determinants in prestimulus modification of acoustic
startle: interaction with ketamine. Psychopharmacology 105:162–168
Midzianovskaia IS (1998) Haloperidol induces changes in the electrocorticogram of rats with genetic
petit mal epilepsy. Zh Vyssh Nerv Deiat Im IP Pavlova 48:1111-1114
Midzianovskaia IS (1999) Two types of spike wave discharges in the electrocorticogram of WAG/Rij
rats, the genetic model of absence epilepsy. Zh Vyssh Nerv Deiat Im IP Pavlova 49:855-859
Miller CL, Bickford PC, Luntz-Leybman V, Adler LE, Gerhardt GA, Freedman R (1992) Phencyclidine
and auditory sensory gating in the hippocampus of the rat. Neuropharmacology 31:1041-1048
Miller CL, Freedman R (1995) The activity of hippocampal interneurons and pyramidal cells during the
response of the HPC to repeated auditory stimuli. Neuroscience 69:371–381
Miyazato H, Skinner RD, Reese NB, Boop FA, Gracia-Rill E (1995) A middle latency auditory evoked
potential. Brain Res Bull 37:247-255
Miyazato H, Skinner RD, Reese NB, Mukawa J, Garcia-Rill E (1996) Midlatency auditory evoked
potentials and the startle response in the rat. Neuroscience 75:289-300
Miyazato H, Skinner RD, Garcia-Rill E (1999a) Sensory gating of the P13 midlatency auditory evoked
potential and the startle response in the rat. Brain Res 822:60-71
Miyazato H, Skinner RD, Garcia-Rill E (1999b) Neurochemical modulation of the P13 midlatency
auditory evoked potential in the rat. Neuroscience 92:911-920
Miyazato H, Skinner RD, Crews T, Williams K, Garcia-Rill E (2000) Serotonergic modulation of the P13
midlatency auditory evoked potential in the rat. Brain Res Bull 51:387-391
Nagamoto HT, Adler LE, Waldo MC, Freedman R (1989) Sensory gating in schizophrenics and normal
controls: effects of changing stimulation interval. Biol Psychiatry 25:549-561
Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R (1996) Gating of auditory P50 in
schizophrenics: Unique effects of clozapine. Biol Psychiatry 40:181-188
Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, Hea R, Griffith J (1999) Auditory
P50 in schizophrenics on clozapine: improved gating parallels clinical improvement
and changes in
plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology 39:10-17
Patterson
JV, Jin Y, Gierczak M, Hetrick WP, Potkin S, Bunney WE, Sandman C (2000) Effects of
temporal variability on P50 and the gating ratio in schizophrenia. Arch Gen Psychiatry
57:57-64
Peng R, Mansbach RE, Braff DL, Geyer MA (1990) A D2 dopamine receptor agonist disrupts
sensorimotor gating in rats: Implications for dopaminergic abnormalities in schizophrenia.
Neuropsychopharmacology 3:211-218
Prinssen
EPM, Balestra, Bemelmans FFJ, Cools AR (1994) Evidence for a role of the shell of the
nucleus accumbens in oral behavior of freely
moving rats. J Neurosci 14:1555-1562
Ralph RJ, Varty GB, Kelly MA, Wang YM, Caron MG, Rubinstein M, Grandy DK, Low MJ, Geyer MA
(1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the
disruption of
prepulse inhibition produced by amphetamine in mice. J Neurosci 19:4627-4633.
Reese
NB, Garcia-Rill E, Skinner RD (1995a) Auditory input to the pendunculopontine nucleus: I.
Evoked potentials. Brain Res Bull 37:257-264
Reese NB, Garcia-Rill E, Skinner RD (1995b) Auditory input to the pendunculopontine nucleus: II. Unit
responses. Brain Res Bull 37:265-273
Rots NY, Cools AR, Berod A, Voorn P, Rostene W, de Kloet ER (1996) Rats bred for enhanced
apomorphine susceptibility have elevated
tyrosine hydroxylase mRNA and dopamine D2-receptor
binding sites in nigrostriatal and tuberoinfundibular dopamine systems. Brain Res 710:189-196
Schwarzkopf
SB, Mitra T, Bruno JP (1992) Sensory gating in rats depleted of dopamine as neonates:
potential relevance to findings in schizophrenic patients. Biol Psychiatry 31:759-773.
Schwarzkopf SB, Lamberti JS, Smith DA (1993) Concurrent assessment of acoustic startle and
auditory P50 evoked potential measures of sensory inhibition. Biol Psychiatry 33:815–828
Sipes TA, Geyer MA (1994) Multiple serotonin receptor subtypes modulate prepulse inhibition of the
startle response in rats. Neuropharmacology 33:441-448
Somogyi P, Bolam JP, Totterdell S, Smith AD (1981) Monosynaptic input from the nucleus accumbensventral
striatum region to retrogradely labeled nigrostriatal
neurons. Brain Res 217:245-263
Starr A, Aguinaldo T, Roe HJ, Michalewski HJ (1997) Sequential changes of auditory processing during
target detection: Motor responding versus mental counting. Electroenceph Clin Neurophysiol
105:201-212
Stevens
KE, Fuller LL, Rose GM (1991) Dopaminergic and noradrenergic modulation on amphetamineinduced
changes
in auditory gating. Brain Res 555:91–98
Stevens KE, Meltzer J, Rose GM (1995) Nicotinic cholinergic normalization of amphetamine-induced
loss of auditory gating in freely moving rats. Psychopharmacology
119:163-170
Stevens KE, Luthman J, Lindqvist EVA, Johnson RG, Rose GM (1996) Effects of neonatal dopamine
depletion on sensory inhibition in the rat. Pharmacol Biochem Behav 53:817–823
Stevens KE, Johnson RG, Rose GM (1997) Rats reared in social isolation show schizophrenia-like
changes in auditory gating. Pharmacol Biochem Behav 58:1031-1036
144

Stevens KE, Wear KD (1997) Normalizing effects of nicotine and a novel nicotinic agonist on
hippocampal auditory gating in two animal models. Pharmacol Biochem Behav 57:869-874
Stevens KE, Nagamoto H, Johnson RG, Adams CE, Rose GM (1998) Conic acid lesions in adult rats as
a model of schizophrenia: changes in auditory information processing. Neuroscience 82:701– 708
Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: A combined
fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321-353
Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Koob GF, Braff DL (1990a) Amphetamine
disruption of PPI of acoustic startle is reversed by depletion of mesolimbic dopamine.
Psychopharmacology 100:413-416
Swerdlow
NR, Braff DL, Masten VL, Geyer MA (1990b) Schizophrenia-like sensorimotor gating
abnormalities in rats following dopamine
infusion into the nucleus accumbens. Psychopharmacology
101:414-420
Swerdlow
NR, Braff DL, Geyer MA (1990c) GABAergic projection from nucleus accumbens to ventral
pallidum mediates
dopamine-induced sensorimotor gating deficits of acoustic startle in rats. Brain
Res 532:146-150
Swerdlow
NR, Keith VA, Braff DL, Geyer MA (1991) Effects of spiperone, raclopride, SCH 23390 and
clozapine on apomorphine
inhibition of sensorimotor gating of the startle response in the rat. J
Pharmacol Exp Ther 256:530-256
Swerdlow
NR, Caine SB, Geyer MA (1992) Regionally selective effects of intracerebral dopamine
infusion on sensorimotor gating of the
startle reflex in rats. Psychopharmacology 108:189-195
Swerdlow NR (1996) Cortico-striatal substrates of cognitive, motor, and sensory gating: speculations
and implication for psychological function and dysfunction. Adv Biol Psychiatry 2:179-207
Van Luijtelaar ELJM, Coenen AML (1986) Two types of electrocortical paroxysms in an inbred strain of
rats. Neuroscience Lett 70:393-397
Varty GB, Higgins GA (1998) dopamine agonist-induced hypothermia and disruption of PPI: evidence
for a role of D3 receptors? Behav Pharmacol
9:445-455
Waldo MC, Adler LE, Freedman R (1988) Defects in auditory sensory gating and their apparent
compensation in relatives of schizophrenics. Schizophrenia
Res 1:19-24
Waldo MC, Cawthry E, Adler LE, Dubester S, Staunton M, Nagamoto H, Baker N, Madison A, Simon J,
Scherzinger A, Drebing C, Gerhardt G, Freedman R (1994) Auditory sensory
gating, hippocampal
volume and catecholamine metabolism in schizophrenics and their siblings. Schizophrenia Res
12:93-106
Waldo
M, Myles Worsley M, Madison A, Byerley W, Freedman R (1995) Sensory gating deficits in
parents of schizophrenics.
Am J Med Genet 60:506-511
Wan FJ, Swerdlow (1993) Intra-accumbens infusion of quinpirole impairs sensorimotor gating of
acoustic startle in rats Psychopharmacology 113:103-109
Wan FJ, Geyer MA, Swerdlow NR (1994) Accumbens D2 modulation of sensorimotor gating in rats:
Assessing anatomical localization. Pharmacol Biochem Behav
49:155-163
Warter JM, Vergnes M, Depaulis A, Tranchant C, Rumbach L, Micheletti G, Marescaux C (1988) Effects
of drugs affecting dopaminergic neurotransmission in rats with spontaneous
petit mal-like seizures.
Neuropharmacology 27:269-274
Wiley
JL (1994) Clozapine’s effects on phencyclidine-induced disruption of prepulse inhibition of the
acoustic startle response. Pharmacol
Biochem Behav 49:1025–1028
Williams DJ, Crossman AR, Slater P (1977) The efferent projections of the nucleus accumbens in the
rat. Brain Res 130:217-227
Zahm DS, Brog JS (1992) On the significance of subterritories in the accumbens part of the ventral
striatum. Neuroscience 50:751-767
Zahm DS (1999) Functional-anatomical implications of the nucleus accumbens core and shell
subterritories. Adv Ventral Striatum Extended
Amygdala 877:133-128
Zouridakis G, Boutros N (1992) Stimulus parameter effects on the P50 evoked response (Brief
Report). Biol Psychiatry 32:839-841
Zouridakis G, Boutros NN, Jansen BH (1997) A fuzzy clustering approach to study the auditory
P50
component in schizophrenia. Psychiatry
Res 69:169-181
145