Premature ejaculation - Keur der Wetenschap
Premature ejaculation - Keur der Wetenschap
Premature ejaculation - Keur der Wetenschap
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Behavioural Brain Research 92 (1998) 111–118<br />
<strong>Premature</strong> <strong>ejaculation</strong> and serotonergic antidepressants-induced delayed<br />
<strong>ejaculation</strong>: the involvement of the serotonergic system<br />
Marcel D. Waldinger a,d, *, Hemmie H.G. Berendsen b , Bertil F.M. Blok c , Berend Olivier d ,<br />
Gert Holstege c<br />
a Department of Psychiatry and Neurosexology, Leyenburg Hospital, Leyweg 275, 2545 CH The Hague, Netherlands<br />
b Department of Neuropharmacology, N.V. Organon, Oss, Netherlands<br />
c Department of Anatomy and Embryology, Faculty of Medicine, Uniersity of Groningen, Groningen, Netherlands<br />
d Department of Psychopharmacology, Rudolf Magnus Institute for Neurosciences, Faculty of Pharmacy, Utrecht Uniersity, Utrecht, Netherlands<br />
Abstract<br />
<strong>Premature</strong> <strong>ejaculation</strong> has generally been consi<strong>der</strong>ed a psychosexual disor<strong>der</strong> with psychogenic aetiology. Although still mainly<br />
treated by behavioural therapy, in recent years double-blind studies have indicated the beneficial effects of some of the<br />
serotonergic antidepressants (SSRIs) in delaying <strong>ejaculation</strong>. We describe here the neurophysiology and the peripheral neuroanatomy<br />
of <strong>ejaculation</strong> and provide a review of the involvement of serotonin in the central nervous system in relation to<br />
serotonergic nuclei and their projections. A hypothesis of the role of 5-HT 1A and 5-HT 2C receptors in premature <strong>ejaculation</strong> is<br />
postulated. © 1998 Elsevier Science B.V. All rights reserved.<br />
Keywords: <strong>Premature</strong> <strong>ejaculation</strong>; Serotonergic antidepressants; Sexual dysfunction<br />
1. Introduction<br />
<strong>Premature</strong> <strong>ejaculation</strong> is defined as a persistent or<br />
recurrent <strong>ejaculation</strong> with minimal sexual stimulation<br />
before, on or shortly after penetration and before the<br />
person wishes it [4]. Generally, premature <strong>ejaculation</strong><br />
was and still is consi<strong>der</strong>ed a psychosexual disturbance<br />
[1,41]. This led to the idea that the main option for<br />
treating premature <strong>ejaculation</strong> were behavioural therapies<br />
such as the stop-start technique [44], the squeeze<br />
technique [33] and other psychotherapeutic interventions<br />
[47]. However, in two longitudinal studies [17,27]<br />
it was shown that the initial positive effects of behavioural<br />
techniques disappear after 3 years.<br />
Pharmacotherapy was also used to delay the <strong>ejaculation</strong><br />
time. Initially, local anesthetic ointments were recommended<br />
[5,16,13], but later case reports and open<br />
trials described the beneficial effects of monoamine-oxi-<br />
* Corresponding author. Tel.: +31 70 3592086; fax: +31 70<br />
3295046.<br />
0166-4328/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.<br />
PII S0166-4328(97)00183-6<br />
dase inhibitors [6], clomipramine [24,23,43,3,26] and<br />
benzodiazepines [42]. However, the use of pharmacotherapy<br />
was consi<strong>der</strong>ed as ‘only’ suppressive for the<br />
disor<strong>der</strong>. The ‘real’ etiology was still thought to be<br />
psychogenic, which is probably one of the reasons that<br />
a neurobiological view regarding aetiology and pathogenesis<br />
is still lacking.<br />
The beneficial effects of the recently introduced selective<br />
serotonergic re-uptake inhibitor antidepressants<br />
(SSRIs), such as fluoxetine [15,55], paroxetine<br />
[55,52,54], and sertraline [34,55] for treating premature<br />
<strong>ejaculation</strong>, clearly indicates that the classical psychological<br />
view of premature <strong>ejaculation</strong> is no longer tenable<br />
as the only pathogenetic theory. Possibly,<br />
serotonin plays a role in the <strong>ejaculation</strong> process. It<br />
might as well be that genetic factors play a role in the<br />
etiology of premature <strong>ejaculation</strong> [56].<br />
This paper first describes the peripheral nervous<br />
pathways associated with the <strong>ejaculation</strong> process, then<br />
reviews the SSRI-induced ejaculatory retardation and<br />
describes some essential features of the serotonergic
112<br />
system. Finally, it will be postulated which serotonin<br />
receptor subtypes might be involved in premature<br />
<strong>ejaculation</strong>.<br />
2. Neurophysiology and peripheral neuroanatomy of<br />
<strong>ejaculation</strong><br />
Ejaculation occurs in two stages [7]. In the first stage,<br />
the emission phase, sympathetic impulses produce peristaltic<br />
smooth muscle contractions of the epididymis<br />
and vas deferens, moving sperm to the posterior (prostatic)<br />
urethra. At the same time, the seminal vesicles<br />
and prostate contract rhythmically, expelling seminal<br />
and prostatic fluid to mix with sperm. Finally, all these<br />
fluids mix with mucus already secreted by the bulbourethral<br />
glands. The combination of these fluids is<br />
known as semen [46]. The emission is subjectively experienced<br />
as ejaculatory inevitability, because at this point<br />
<strong>ejaculation</strong> cannot be stopped. It is immediately followed<br />
by the second phase, the expulsion or <strong>ejaculation</strong><br />
proper, in which semen is expelled out of the urethra by<br />
rhythmic contractions of pelvic floor muscles.<br />
The (preganglionic) sympathetic nerves, involved in<br />
the emission phase, originate from the intermediolateral<br />
columns of the spinal thoracolumbar cord from T10 to<br />
L2 [32] and travel via the sympathetic chain and hypogastric<br />
nerve (postganglionic) to the pelvic plexus (inferior<br />
hypogastric plexus) or via the sympathetic chain<br />
and pelvic nerve (nervi erigentes) to the pelvic plexus<br />
[18]. From the pelvic plexus the sympathetic nerves are<br />
mediated via the cavernous nerve to the vase deferentia<br />
[18].<br />
During emission the sphincter urethrae internus muscle<br />
(blad<strong>der</strong> neck) contracts by sympathetic influence,<br />
preventing the semen to enter the blad<strong>der</strong> (retrograde<br />
<strong>ejaculation</strong>). The second phase is initiated by pressure<br />
on the wall of the ampullae urethrae by the semen,<br />
giving rise to afferent impulses which reach the S2–S4<br />
sacral cord segments via the pudendal and pelvic nerves<br />
[40]. The expulsion is mediated by motoneurons in the<br />
nucleus of Onuf, which, by way of the pudendal nerve<br />
[45] produce co-ordinated contractions of the bulboand<br />
ischiocavernosus muscles of the pelvic floor. How<br />
the afferent impulses of the urethral wall are relayed to<br />
the motoneurons of Onuf’s nucleus is not known.<br />
The ejaculatory response is triggered by genital and<br />
cortical stimulation. In genital stimulation the afferent<br />
sensory impulses are mediated via touch receptors on<br />
the glans penis, which are connected with sensory fibers<br />
that travel in the dorsal penile and pudendal nerves and<br />
enter the sacral spinal cord. How cortical activation,<br />
such as visual and auditory impulses, reach the <strong>ejaculation</strong><br />
related systems is not known.<br />
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118<br />
3. Peripheral serotonin and the central nervous system<br />
The first indication of the presence of serotonin dates<br />
from more than 100 years ago, when a vasoconstrictive<br />
agent in blood was accidentally discovered, which later<br />
appeared to be present in serum. In the 1930s, an agent<br />
(enteramine) was discovered in the gut [20], but it was<br />
not clear whether this agent was the same as that found<br />
in serum. By the end of the 1940s this endogenous<br />
factor was identified. After purification it was called<br />
‘serotonin’ because of its ‘serum tonic’ properties. In<br />
1952, it became clear that serotonin or 5-hydroxytryptamine<br />
(5-HT; [39]) and enteramine were identical<br />
[19].<br />
4. Peripheral serotonin<br />
The majority of 5-HT is found in the enterochromaffin<br />
cells in the gastrointestinal tract, where it accounts<br />
for approximately 80% of total body 5-HT<br />
content [14,21]. In the periphery 5-HT acts as a vasoconstrictor<br />
and pro-aggregator when released from aggregating<br />
platelets, as a neurotransmitter in the enteric<br />
plexuses of the gut and as an autocrine hormone when<br />
released from enterochromaffin cells from the gut, pancreas<br />
and elsewhere [25,21]. Circulating 5-HT does not<br />
enter the brain because it cannot cross the blood–brain<br />
barrier.<br />
5. Serotonin in the central nervous system<br />
After the discovery that 5-HT occurred in the central<br />
nervous system also [51], Woolley and Shaw [57] postulated<br />
in 1954, a central role for 5-HT in psychiatric<br />
disor<strong>der</strong>s, in particular because the 5-HT agonist D-<br />
LSD exerted such a potent psychomimetic action. Reserpine,<br />
a drug given in serious hypertension, was<br />
found to induce a depressive mood. As reserpine induces<br />
an initial release of 5-HT from presynaptic terminals<br />
followed by the ceasing of 5-HT release, a relation<br />
was suggested between low 5-HT levels and depression.<br />
Further research has led to the hypothesis that a deficit<br />
in monoamines (including 5-HT) could lead to depression.<br />
This theory has led to the development of the<br />
selective serotonin re-uptake inhibitors (SSRIs) which<br />
proved to be effective antidepressants. The serotonin<br />
system in the brain was visualized using histochemical<br />
techniques (Falck–Hillarp techniques) in the 1960s.<br />
This relatively primitive localization method was<br />
strongly improved by the development of antibodies<br />
against 5-HT [48] and later still, by autoradiographic<br />
techniques, which made it possible to reveal detailed<br />
5-HT receptor locations.
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118 113<br />
Fig. 1. A schematic representation of a serotonergic neuron and a post-synaptic neuron. All known 5-HT receptors and their putative localization<br />
are depicted (hypothetical).<br />
In 1979, using radioligand binding technology, two<br />
classes of 5-HT receptors in the CNS were shown [38].<br />
This was the start of an era in which a continuous<br />
stream of new 5-HT receptors has been detected.<br />
Presently, at least sixteen different 5-HT receptors have<br />
been found, cloned and the structure described (5-<br />
HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 1D, 5-HT 1E, 5-HT 1F,<br />
5-HT 2A, 5-HT 2B, 5-HT 2C, 5-HT 3, 5-HT 4, 5-HT 5A, 5-<br />
HT 5B, 5-HT 6, 5-HT 7). A schematic representation of<br />
these different 5-HT receptors and their putative locations<br />
are depicted on a cartoon of a 5-HT presynaptic<br />
neuron and a post-synaptic neuron (Fig. 1).<br />
5.1. Serotonergic neurons<br />
Serotonergic cell bodies are present in the brainstem<br />
in the raphe nuclei and adjacent reticular formation<br />
(Fig. 2). There is a clear dichotomy in the 5-HT system<br />
neuronal cell groups. Firstly, a rostral part with cell<br />
bodies in the midbrain and rostral pons projecting to<br />
the forebrain. Secondly, a caudal part with cell bodies<br />
predominantly in the medulla oblongata with important<br />
projections to the spinal cord. Both parts also<br />
project to areas in the brainstem and the cerebellum<br />
[31].<br />
5.2. Rostral and caudal serotonergic cell groups<br />
The rostral part of the 5-HT system consists of the<br />
caudal linear nucleus and the dorsal and median raphe<br />
nuclei. The number of 5-HT cells in the dorsal raphe is<br />
the largest among all raphe nuclei and contains approx-<br />
imately 24 000 in the cat and 165 000 in man [50].<br />
Besides the raphe nuclei, a number of 5-HT neurons are<br />
present in the adjoining reticular formation of pons and<br />
midbrain. The caudal system contains the nuclei raphe<br />
magnus, pallidus and obscurus and some in the adjoining<br />
medullary reticular formation, solitary nucleus and<br />
the area of the nucleus (sub)coeruleus.<br />
5.3. Projections of the serotonergic cell groups<br />
5.3.1. Ascending projections<br />
The ascending 5-HT system consists of two more or<br />
less parallel projection pathways, presumably with different<br />
functions [50].<br />
The first system is called ‘Basket-axon’ system and<br />
originates in the median raphe nucleus. It has thick<br />
fibers (M-fibers) that branch into short, thin fibers and<br />
form large, round boutons (varicosities) with extensive<br />
synaptic contacts. These beaded axons often intensively<br />
embranch certain cortical cells (baskets) and form classical<br />
synaptic contacts.<br />
The second system originates in the dorsal raphe<br />
nucleus. It has thin fibers (D-fibers) with many spindlesized<br />
varicosities. These fibers branch extensively and<br />
diffusely and contain small fusiform boutons. However,<br />
these boutons do not seem to contain real synaptic<br />
structures.<br />
Both systems (M- and D-fibers) can be found together<br />
in most brain areas, but to a different extent.<br />
The cerebral cortex is the area where both systems<br />
co-exist extensively, whereas the striatum almost exclusively<br />
receives fine varicose D-fibers and the gyrus
114<br />
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118<br />
Fig. 2. A longitudinal view of rat brain with a schematic representation of the localization of the serotonergic cell bodies in the raphe nuclei and<br />
in the brain stem reticular formation and the corresponding classification into the B-groups and their projections. CB, cerebellum; mfb, medial<br />
forebrain bundle, CC, corpus callosum; OB, olfactory bulb; Cpu, caudate putamen; OC, optic chiasma; GP, globus pallidus; OT, olfactory<br />
tubercle; H, hypothalamus; Pit, pituitary gland; Hip, hippocampal region; Sc, superior colliculus; lc, locus coeruleus; SN, substantia nigra; LS,<br />
lateral septal nucleus; T, thalamus; MM, medial mammilary nucleus; V, ventrikel. For the 5-HT cell cluster, the 5-HT cells in structure<br />
(classification into the rostral (r) and caudal (c) serotonergic system according to Tork (1991) are as follows: B1, raphe pallidus nucleus (c), caudal<br />
ventrolateral medulla (c); B2, raphe obscurus nucleus (c); B3, raphe magnus nucleus (c), rostral ventrolateral medulla (c), lateral paragigantocellular<br />
reticular nucleus (c); B4, raphe obscurus, dorsolateral part (c); B5, median raphe nucleus, caudal part (r); B6, dorsal raphe nucleus, caudal<br />
part (r); B7, dorsal raphe nucleus, rostral part (r); B8, Median raphe nucleus, rostral part (r); caudal linear nucleus (r); B7, nucleus pontis oralis<br />
(r); B9, Nucleus pontis oralis (r); Supralemniscal region (r).<br />
dentatus primarily thick M-fibers. The functional role<br />
of these two 5-HT systems is rather unclear, although<br />
they display a differential sensitivity for certain substituted<br />
amphetamines like MDMA [37]. Such drugs destroy<br />
the fine varicose system but leave the thick,<br />
beaded system intact.<br />
5.3.2. Descending projections<br />
The caudal raphe nuclei project to the caudal brain<br />
stem and spinal cord. The raphe magnus nucleus predominantly<br />
projects to the dorsal horn and the nuclei<br />
raphe pallidus and obscurus to the ventral horn, intermediate<br />
zone and the intermediolateral cell column<br />
(IML) of the thoracolumbar and sacral spinal cord.<br />
The latter areas contain preganglionic sympathetic and<br />
parasympathetic motoneurons, respectively.<br />
5.3.3. Afferents of the caudal serotonergic raphe nuclei<br />
The afferents of the caudal raphe nuclei originate<br />
largely from medial structures in the so called limbic<br />
system. The most important are the mesencephalic periaqueductal<br />
grey and medial cell groups in hypothalamus<br />
and pre-optic area [28].<br />
5.3.4. Regulation<br />
Serotonergic neurons have various mechanisms to<br />
regulate their own activity, viz. somatodendritic autoreceptors<br />
(5-HT 1A receptors), presynaptic autoreceptors<br />
(5-HT 1B/1D receptors) and the 5-HT re-uptake process<br />
(5-HT transporter).<br />
5.3.4.1. Somatodendritic (5-HT 1A) autoreceptors. The<br />
5-HT 1A autoreceptors are present in high densities on<br />
the cell bodies and dendrites of serotonergic neurons in<br />
the raphe nuclei (Fig. 3). Upon activation of these<br />
receptors, the firing rate of the 5-HT neuron decreases.<br />
Un<strong>der</strong> normal physiological conditions endogenous 5-<br />
HT activates this 5-HT 1A autoreceptor. It is as yet not<br />
clear from where this endogenous 5-HT originates, but<br />
it is assumed that it <strong>der</strong>ives from somatodendritic release,<br />
which differs from synaptic release. Application<br />
of the selective 5-HT 1A receptor agonists (i.e. 8-OH-<br />
DPAT or flesinoxan) either systemically or locally in<br />
the raphe nuclei, inhibits the release of 5-HT in the<br />
synaptic cleft.<br />
5.3.4.2. 5-HT 1B/1D autoreceptors. This pre-synaptic receptor<br />
inhibits, after activation, the 5-HT release into<br />
the synaptic cleft. The 5-HT 1B/1D receptor is coupled to<br />
an inhibitory (GI-protein) transaction mechanism that<br />
apparently blocks the release of 5-HT from the synaptic<br />
vesicles in an as yet not un<strong>der</strong>stood manner. This<br />
feedback mechanism of the cell, where the released<br />
5-HT inhibits its own release, is a frequently occurring<br />
principle in neurotransmitter regulation and provides<br />
the system with the possibility to prevent overstimulation<br />
of (post)synaptic receptors.<br />
5.3.4.3. 5-HT re-uptake. If 5-HT is released into the<br />
synaptic cleft it should be removed again as fast as<br />
possible to prevent overstimulation of the<br />
(post)synaptic receptors (desensitization). The 5-HT<br />
neuron, therefore, possesses large quantities of 5-HT<br />
transporters (5-HTT), not only on the synaptic endings<br />
but also on the cell bodies and dendrites of serotonergic<br />
neurons. Apart from this 5-HT cell system, glial cells<br />
have also a transport system which presumably contributes<br />
to the remove of released 5-HT. After blockade<br />
of the 5-HT transporters via selective serotonin re-uptake<br />
inhibitors (SSRIs), the synaptic 5-HT increases,
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118 115<br />
Fig. 3. Schematic representation of acute and chronic activation SSRI administration and the effect on the 5-HT 1A autoreceptor.<br />
although this process is counteracted by activation of<br />
5-HT 1A autoreceptors, which are stimulated by enhanced<br />
5-HT and inhibit the 5-HT release.<br />
5.3.4.4. Acute and chronic administration of SSRIs. After<br />
acute administration of an SSRI all 5-HT transporters<br />
are blocked. This leads to high 5-HT levels in<br />
the extracellular space around the 5-HT cell bodies in<br />
the raphe nuclei, leading to activation of 5-HT 1A autoreceptors<br />
and thus to a decrease in the firing frequency<br />
of the cell and a decreased release of 5-HT in<br />
the synaptic cleft. This decreased release is (completely<br />
or partially) compensated by blockade of the<br />
5-HT re-uptake in the synaptic cleft. The net effect in<br />
the synaptic cleft is difficult to predict, both an increase<br />
in or lack of effect have been observed. If a<br />
post-synaptic increase occurs, activation of the presynaptic<br />
5-HT 1B/1D autoreceptor will further dampen<br />
the release process. In general, acute administration of<br />
SSRIs will presumably lead to a mild increase of 5-<br />
HT neurotransmission leading to some stimulation of<br />
all post-synaptic 5-HT receptors.<br />
After chronic administration a number of adaptive<br />
processes may play a role, although much is still quite<br />
speculative. Because the 5-HTTs are chronically<br />
blocked, a chronically enhanced level of 5-HT is<br />
present at somatodendritic level. This leads to desensitization<br />
of the 5-HT 1A receptors and consequently to<br />
lesser (or no) inhibition of the cell firing of the 5-HT<br />
neuron, leading to higher 5-HT release. Simultaneously,<br />
also the synaptic 5-HTTs are chronically<br />
blocked which means, together with the enhanced re-<br />
lease of 5-HT, to strongly enhanced synaptic levels of<br />
5-HT. It is possible, although not fully elucidated yet,<br />
that the 5-HT 1B/1D autoreceptors also desensitize,<br />
which might contribute to the process of enhanced<br />
5-HT neurotransmission. The net effect of chronic<br />
SSRI administration is thus a strongly enhanced 5-HT<br />
neurotransmission. Apparently, activation of one (or<br />
more) of the post-synaptic 5-HT receptors, contributes<br />
to the antidepressant and anxiolytic effects of the SS-<br />
RIs.<br />
6. <strong>Premature</strong> <strong>ejaculation</strong> and 5-HT<br />
Some of the SSRIs appear effective in inhibiting the<br />
premature <strong>ejaculation</strong> both after acute and chronic<br />
administration [55,52,54,53] whereas their antidepressant<br />
and anxiolytic effects only gradually emerge over<br />
time. This remarkably rapid onset is not well un<strong>der</strong>stood.<br />
It is suggested that acute blockade of 5-HT<br />
re-uptake enhances 5-HT transmission into the<br />
synapse. These acute synaptic effects occur within<br />
hours of administering antidepressant SSRIs. Since<br />
the rapid onset of postponement of <strong>ejaculation</strong> by<br />
SSRIs has a similar time course as the synaptic effects<br />
it is suggested that the postponement of <strong>ejaculation</strong> is<br />
mediated by the acutely enhanced 5-HT neurotransmission.<br />
Apart from their rapid onset of action, the question<br />
remains why SSRIs, such as paroxetine [55,52,54],<br />
fluoxetine [55], sertraline [34,55] and to a lesser extent<br />
also fluvoxamine [55] delay <strong>ejaculation</strong> time. Human<br />
<strong>ejaculation</strong> is peripherally activated by 1-noradrener-
116<br />
gic nerve stimulation. Since paroxetine has no sympatholytic<br />
effects, it is suggested that the effect of paroxetine<br />
on the delay of <strong>ejaculation</strong> is on the central<br />
nervous system.<br />
The involvement of the central serotonergic neurotransmission<br />
in human <strong>ejaculation</strong> has been investigated<br />
in animal studies. Induction of penile erections<br />
in rats and rhesus monkeys showed that responses<br />
due to SSRI treatment are identical to those seen<br />
after selective activation of 5-HT 2C receptors [49,8,12]<br />
and are different from the responses seen after 5-<br />
HT 1A and 5-HT 2A receptor stimulation [58,11,36,30].<br />
Moreover, a cross familiarization study showed that<br />
the drug stimuli of the SSRI’s fluoxetine and paroxetine<br />
most resemble those of a 5-HT 2C-receptor agonist<br />
[10]. Apparently, it seems that the responses from<br />
SSRI treatment in these animals are due to 5-HT 2C<br />
receptor activation [12,49]. Since paroxetine treatment<br />
results in <strong>ejaculation</strong> retardation, it is suggested that<br />
in humans premature <strong>ejaculation</strong> is caused by hyposensitivity<br />
of 5-HT 2C receptors. Such a concept<br />
would correspond with the results of rat studies in<br />
which the 5-HT receptor agonists D-LSD (D-lysergic<br />
acid diethylamide) and quipazine increase the <strong>ejaculation</strong><br />
latency [2]. Furthermore, DOI (2,5-dimethoxy-4iodophenyl-2-aminopropane)<br />
which equally stimulates<br />
5-HT 2A and 5-HT 2C receptors, also increases the <strong>ejaculation</strong><br />
latency [22], while the selective 5-HT 2A receptor<br />
agonist DOM (2,5-dimethoxy-4-methylamphetamine)<br />
does not have this effect [2].<br />
In male rats also another 5-HT subtype receptor<br />
seems to be involved in the <strong>ejaculation</strong> process. Activation<br />
of 5-HT 1A receptors by the selective 5-HT 1A<br />
receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-npropylaminotetralin)<br />
shortens the <strong>ejaculation</strong> latency<br />
time and reduces the number of intermissions preceding<br />
<strong>ejaculation</strong> in animals [2]. The behavioral response<br />
to activation of 5-HT 1A receptors is attenuated or<br />
completely blocked by co-activation of 5-HT 2C receptors<br />
indicating that functional interactions between<br />
these receptors exists [9]. Extrapolating these findings<br />
from animal research to human premature <strong>ejaculation</strong><br />
one might speculate that premature <strong>ejaculation</strong> may<br />
be caused by the hypersensitive 5-HT 1A receptor.<br />
Treatment of premature <strong>ejaculation</strong> by an SSRI will<br />
then induce activation of the 5-HT 2C receptor and<br />
consequently decrease the function of the 5-HT 1A receptor<br />
or restore the balance between 5-HT 1A and<br />
5-HT 2C receptor function, resulting in an overall delay<br />
of <strong>ejaculation</strong>.<br />
However, the identification of which specific 5-HT<br />
receptor subtypes are involved in the human <strong>ejaculation</strong><br />
process is only possible by administration of subtype<br />
selective 5-HT ligands in patients with premature<br />
<strong>ejaculation</strong>. Unfortunately, these agents are not yet<br />
available for human use.<br />
M.D. Waldinger et al. / Behaioural Brain Research 92 (1998) 111–118<br />
7. SSRIs and their neurophysiological substrates of<br />
sexual side effects<br />
Although it is well known that SSRIs have sexual<br />
side effects in humans, such as retardation of <strong>ejaculation</strong><br />
and anorgasmia [35], the neural substrates involved<br />
in these effects are unknown. The bulk of<br />
psychopharmacological studies using SSRIs for depression,<br />
anxiety disor<strong>der</strong>s or the obsessive-compulsive<br />
disor<strong>der</strong> have investigated their effects on serotonergic<br />
neurons and their projections to cortical and subcortical<br />
structures. However, studying sexual effects of SS-<br />
RIs, such as their effect on <strong>ejaculation</strong>, necessitates<br />
studies not only on cortical and subcortical functions,<br />
but also on brainstem functions, spinal cord mechanisms<br />
and the peripheral nervous system.<br />
The recent description of the emotional motor system<br />
(EMS) by Holstege [28,29] might represent a neuroanatomical<br />
substrate for the emotional influences on<br />
basic neurogenital pathways. Further research into the<br />
relationship between the central serotonergic system<br />
and the EMS might illuminate the speculative idea<br />
that a threshold for <strong>ejaculation</strong> is set and modulated<br />
somewhere in the central nervous system and can be<br />
changed by SSRI treatment.<br />
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