European European Urology 48 (2005) 408–417

Urology

ReviewErectile Dysfunction/Andrology
Physiology of Ejaculation: Emphasis on
Serotonergic Control
François Giulianoa,b,*, Pierre Clémenta
a
Pelvipharm, Domaine CNRS, 1 Avenue de la terrasse, Bâtiment 5, 91190 Gif sur Yvette, France
b
Groupe de Recherche en Urologie, UPRES, EA 1602, University of Paris South, 63 rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France
Accepted 20 May 2005
Available online 20 June 2005

Abstract
Ejaculation is constituted by two distinct phases, emission and expulsion. Orgasm, a feature perhaps unique in
humans, is a cerebral process that occurs, in normal conditions, concomitantly to expulsion of semen. Normal
antegrade ejaculation is a highly coordinated physiological process with emission and expulsion phases being under
the control of autonomic and somatic nervous systems respectively. The central command of ejaculation is located at
the thoracolumbar and lumbosacral levels of the spinal cord and is activated by stimuli from genital, mainly penile,
origin although cerebral descending pathways exert both inhibitory and excitatory regulatory roles. Cerebral
structures specifically activated during ejaculation form a tightly interconnected network comprising hypothalamic,
diencephalic and pontine areas. A rational neurobiological approach has led to identify several neurotransmitters
contributing to the ejaculatory process. Amongst them, serotonin (5-HT) has received strong experimental
evidences indicating its inhibitory role in the central control of ejaculation. In particular, 5-HT1A cerebral
autoreceptors but also spinal 5-HT1B and, in a lesser extent, 5-HT2C receptors have been shown to mediate
the effects of 5-HT on ejaculation. Pharmacological strategies, especially those targeting serotonergic system, for
the treatment of ejaculatory disorders in human will undoubtedly benefit from the application of basic and clinical
research findings. In this perspective, the use of selective serotonin reuptake inhibitors (SSRIs) which basically
increase the amount of central 5-HT and delay ejaculation in humans seems promising.
# 2005 Elsevier B.V. All rights reserved.

Keywords: Ejaculation; Physiology; Neuroanatomy; Serotonin

1. Introduction In recent years, male sexual dysfunctions have

Amongst the different physiological functions, those
related to reproduction are probably the unique essen-
tial for survival of the human species without being
vital for the individual. Thus, from an evolutionist
perspective, the rewarding sensory expression repre-
sented by orgasm occurring concomitantly with eja-
culation is an advantage for the perpetuation of the
human race.
* Corresponding author. Present address: Department of Urology, Aca-
demic Hospital of Bicetre, 78 Rue du General Leclerc, 94270 Le Kremlin
Bicetre Cedex, France. Tel. +33 145213698; Fax: +33 145212170.
E-mail address: giuliano@cyber-sante.org (F. Giuliano).
0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2005.05.017
become a topic of interest in biological science. How-
ever, animal and clinical studies have focused on
mechanisms and pathophysiology of penile erection
whereas the ejaculatory process and its dysfunctions
remained poorly investigated. Epidemiological studies
performed to date in European countries and the USA
have reported high prevalence for ejaculatory disor-
ders, mainly premature but also delayed and painful
ejaculation [1–5]. Since decades, ejaculatory disorders
were assumed to be psychological or urological issues
but recently a proposal has emerged that considers
these disorders as possibly having a neurobiological
substratum [6]. Owing to the fact that aetiology of
ejaculatory dysfunction is multiple (including psycho-
 F. Giuliano, P. Clément / European Urology 48 (2005) 408–417
logical or organic origins) [7], it can be claimed that it
is a multifactorial disorder.
The organisation of anatomical structures implicated
in ejaculation fundamentally shows common features in
mammalians including humans. Therefore, the devel-
opment of an experimental approach is useful for under-
standing the human physiology of ejaculation and may
allow the discovery of potential pharmacological thera-
pies applicable for the treatment of ejaculatory dysfunc-
tions. Ejaculation, usually accompanied by orgasm, is
constituted by two successive phases, emission and
expulsion, which involve different pelvi-perineal anato-
mical structures. A tight coordination of sympathetic,
parasympathetic as well as somatic divisions of the
nervous system is necessary for normal antegrade eja-
culation to occur.
2. Physiology of ejaculation
The importance of the autonomic nervous system in
regulating ejaculatory process is well documented [8–
10]. Two groups of anatomical structures involved in
ejaculation can be distinguished depending on the
phase they participate in (i.e. emission or expulsion).
The organs involved in the emission phase comprise
epididymis, vas deferens, seminal vesicles, prostate
gland, prostatic urethra and bladder neck. The organs
participating to the expulsion phase comprise bladder
neck and urethra again as well as pelvic striated
muscles.
2.1. Emission
Emission denotes the ejection into the posterior
urethra of spermatozoa mixed with products secreted
by accessory sexual glands. During the emission phase,
both epithelial secretion and smooth muscle cells
contraction take place throughout the seminal tract
in a sequential manner [11]. All of the organs partici-
pating to emission phase receive a dense autonomic
innervation composed of sympathetic and parasympa-
thetic axons mainly coming from the pelvic plexus
(occasionally referred to as the inferior hypogastric
plexus in humans). In humans, the pelvic plexus is
situated retroperitoneally in the sagittal plane on either
side of the rectum and lies lateral and posterior to the
seminal vesicles [12]. It contains neural fibres rostrally
conveyed by both pelvic and hypogastric nerves and
from the caudal paravertebral sympathetic chain [13].
The predominant role in commanding emission is
played by sympathetic nerves with their terminals
releasing norepinephrine although acetylcholine, oxy-
tocin and non-adrenergic/non-cholinergic (NANC)
409
factors including ATP [14–16], neuropeptide Y (NPY)
[17,18], vasoactive intestinal peptide (VIP) [19,20],
and nitric oxide (NO) [20–22] are also important
mediators within sexual glands. The important role
of the hypogastric nerves in controlling emission is
illustrated by the fact that isolated lesion of these
nerves in human, that may result from dissection of
para-aortic lymph nodes in the treatment of testicular
carcinoma, prevents seminal emission [23]. In addi-
tion, electric stimulation of the superior hypogastric
plexus, which corresponds to a network of nerve
bundles running in front of the lower abdominal aorta,
in paraplegic men was reported to cause seminal
emission [23]. Stimuli from the genitalia, essentially
those reflecting the degree of activation of sensory
receptors mainly located in the penile glans, are inte-
grated at the spinal level and stimulate emission [24].
The emission phase of ejaculation is under consider-
able cerebral control and may be elicited following
visual and physical erotic stimulations [25].
2.2. Expulsion
Expulsion represents the ejection of sperm from
urethra at the glans meatus. Expulsion is, according
to a generally accepted idea, a spinal cord reflex that
occurs as the ejaculatory process reaches a ‘‘point of no
return’’. During expulsion phase, smooth muscle fibres
of the bladder neck contract to prevent semen to flow
backward into the bladder, and the pelvic floor mus-
cles, with bulbospongiosus and ischiocavernosus
muscles playing primary roles, display stereotyped
rhythmic contractions to propel semen distally
throughout bulbar and penile urethra [26]. Normal
antegrade ejaculation also requires the external urinary
sphincter to relax. Bladder neck and proximal part of
urethra, both containing abundant smooth muscle
fibres, receive a dual sympathetic and parasympathetic
innervation. In addition to cholinergic and noradrener-
gic components, the presence of nerve terminals con-
taining NPY, VIP and NO-synthase has also been
evidenced in these anatomical structures in rodents
and humans [27–31]. The external urethral sphincter
and pelvic floor striated muscles are solely commanded
by the somatic nervous system. Nevertheless, there are
no convincing data for a voluntary control of the
expulsion phase in humans.
The trigger of rhythmic pelvic striated muscles
contractions responsible for the expulsion of sperm
is still not clearly identified. It has been proposed that
expulsion phase of ejaculation is a reflex response to
the presence of semen into the bulbous urethra [32].
However, several lines of experimental and clinical
evidence do not support this view in demonstrating that
410 F. Giuliano, P. Clément / European Urology 48 (2005) 408–417

urethral stimulation by ejaculate does not contribute to

the regulation of the striated muscle components of
ejaculation [26,33,34]. These data together with recent
findings of a potential spinal ejaculatory generator in
rat [35] lead us to rather postulate that a continuum
exists in the physiological process of ejaculation with
emission inevitably followed by expulsion once the
threshold of spinal activation has been reached.

2.3. Orgasm
The human sexual response cycle consists of four
distinct stages which are desire, arousal, orgasm, and
resolution with the orgasmic stage as the shortest but
most intense of the four [36]. The orgasm is undoubt-
edly one of the most pleasurable sensations known to
humankind and has been associated with reward in rats
[37] although very little is known about the underlying
physiological mechanisms that control orgasmic
responses. Orgasm is a cerebral process that usually
follows a series of peripheral physical events compris-
ing contraction of accessory sexual organs and urethral
bulb, build-up and release of pressure in distal urethra.
It is noteworthy that orgasm is usually reported by
patients after radical prostatectomy [38,39] or after
lesion of the hypogastric plexus causing failure of
seminal emission [23]. Furthermore, orgasmic sensa-
tions generated cerebrally without input from genitals
or without ejaculation have been reported for a long
time [40]. These data indicate that the emission of
sperm and its progression through the urethra are likely
not sine qua non conditions for orgasm to occur.
3. Neuroanatomical organisation of the
circuitry of ejaculation
The sympathetic and parasympathetic nervous sys-
tems, closely interconnected into the pelvic plexus
which represents an integrative peripheral crossroad
site, act in synergy to command physiological events
occurring during ejaculation. Both sympathetic and
parasympathetic tones are under the influence of sen-
sory genital and/or cerebral erotic stimuli integrated
and processed at the spinal cord level (Fig. 1).
3.1. Peripheral nervous pathways
3.1.1. Afferents
The dorsal nerve of the penis, a sensory branch of
the pudendal nerve, conveys impulses to upper sacral
and lower lumbar segments of the spinal cord from
sensory receptors harboured in the penile skin, pre-
puce, and glans [41,42]. Encapsulated receptors
(Krause-Finger corpuscles) have been found in the
Fig. 1. Neural pathways controlling ejaculation. Sympathetic (S), para-
sympathetic (PS), and somatic nerves originating in lumbosacral spinal
nuclei command the peripheral anatomical structures responsible for eja-
culation. Sensory afferents originating in genital areas are integrated at the
spinal and brain levels. Activity of spinal preganglionic and motor neurones
is under the influence of peripheral and supraspinal inputs. Abbreviations:
BN, bladder neck; BS, bulbospongiosus muscle; Ep, epididymis; P, prostate;
SV, seminal vesicle; VD, vas deferens.
human glans but the majority of afferent terminals
are represented by free nerve endings [43]. Stimulation
of the Krause-Finger corpuscles, which can be poten-
tiated by sensory information coming from various
peripheral areas such as penile shaft, perineum, and
testes, facilitates ejaculation. In different mammalian
species, a relatively sparse sensory innervation of
ductus deferens, prostate, and urethra has been evi-
denced which reaches the lumbosacral spinal cord also
via the pudendal nerve [44,45]. A second afferent
pathway is constituted by sensory fibres travelling
along the hypogastric nerve and, after passing through
the paravertebral lumbosacral sympathetic chain,
entering the spinal cord via thoracolumbar dorsal roots
[46]. Sensory afferents terminate in the medial dorsal
horn and the dorsal grey commissure of the spinal cord
[47,48] although a direct projection to ventral horn
motoneurones has been reported in rats [41].
3.1.2. Efferents
The soma of the preganglionic sympathetic neu-
rones involved in the control of ejaculation are located
in the intermediolateral cell column and in the central
 F. Giuliano, P. Clément / European Urology 48 (2005) 408–417
autonomic region of the thoracolumbar segments of the
rat and cat spinal cord [49,50]. The sympathetic fibres,
emerging from the thoracolumbar spinal column via
the ventral roots, travel in the paravertebral sympa-
thetic chain. In the majority of mammalian species, the
fibres then proceed whether directly via the splanchnic
nerves or after relaying in the coeliac superior mesen-
teric ganglia via the intermesenteric nerves to the
inferior mesenteric ganglia [51]. Emanating from the
inferior mesenteric ganglia are the hypogastric nerves
that form, after joining the pelvic nerves, the right and
left pelvic plexi from which arise fibres innervating
anatomical structures involved in ejaculation.
The cell bodies of the preganglionic parasympa-
thetic neurones lie in human and in various mammalian
species in the intermediolateral cell column of the
sacral segments of the spinal cord in an area referred
to as the sacral parasympathetic nucleus (SPN) [52].
The SPN neurones send axons, travelling in the pelvic
nerve, to the postganglionic cells located in the pelvic
plexus.
Axons of motoneurones, which cell bodies are found
at the lumbosacral spinal level in the Onuf’s nucleus,
exit the ventral horn of the spinal cord and proceed via
the motor branch of the pudendal nerve to the pelvic
floor striated muscles, including bulbospongiosus and
ischiocavernosus muscles [53].
3.2. Spinal network
The thoracolumbar sympathetic as well as the sacral
parasympathetic (specifically the SPN) and somatic
(Onuf’s nucleus) spinal ejaculatory nuclei, play a
pivotal role in ejaculation as they integrate peripheral
and cerebral signals and sends coordinated outputs to
pelvi-perineal anatomical structures that lead to a
normal ejaculatory process to occur. Integrity of these
spinal nuclei is necessary and sufficient for the expres-
sion of ejaculation as demonstrated by induction of the
ejaculatory process after peripheral stimulation in ani-
mals and humans with spinal cord injuries located
about these nuclei [32,54]. The conversion of sensory
information into secretory and motor autonomic and
somatic outputs involves spinal interneurones which
have been recently characterised in rats [35]. The
presence of these cells, designated as lumbar spinotha-
lamic (LSt) cells, has been demonstrated in laminae X
and VII of the spinal lumbar segments 3 and 4.
Immunohistochemical investigations have shown that
LSt cells contain galanin, cholecystokinin, and enke-
phalin. In rat spinal cord, fibres of the sensory branch of
the pudendal nerve terminate close to LSt cells [47],
although a direct connection has not been proved yet.
LSt neurones project to the parvocellular subparafas-
411
cicular nucleus of the thalamus (SPFp) [55,56] and
anatomical data indicate that these cells may also
project to the sympathetic and parasympathetic preg-
anglionic neurones innervating the pelvis [57,58].
3.3. Brain network
As a centrally integrated and highly coordinated
process, ejaculation involves cerebral sensory areas
and motor centres which are tightly interconnected.
Animal studies investigating Fos protein pattern of
expression, have revealed, in distinct species, brain
structures specifically activated when the animals dis-
played ejaculation [59–62]. This was further confirmed
by a study using a serotonin (5-HT) 1A subtype
receptor agonist (8-OH-DPAT) as a pro-ejaculatory
pharmacological agent in rats [63]. As a whole, these
data strongly suggest the existence of a cerebral net-
work specifically related to ejaculation that is activated
whatever the preceding sexual activity, i.e. mounts and
intromissions in rats (Fig. 2). The brain structures
belonging to this cerebral network comprise discrete
regions lying within the posteromedial bed nucleus of
stria terminalis (BNSTpm), the posterodorsal medial
amygdaloid nucleus (MeApd), the posterodorsal pre-
optic nucleus (PNpd), and the parvicellular part of the
subparafascicular thalamus (SPFp). Reciprocal con-
Fig. 2. Diagram of brain structures and putative central pathways involved
in ejaculation. In grey are indicated the structures containing serotonin auto/
heteroreceptors. Abbreviations: BNSTpm, posteromedial bed nucleus of
stria terminalis; MeApd, posterodorsal medial amygdaloid nucleus; MPOA,
medial preoptic area; PAG, periaqueductal grey; nPGi, paragigantocellular
nucleus; PNpd, posterodorsal preoptic nucleus; PVN, paraventricular tha-
lamic nucleus; SPFp, parvicellular part of the subparafascicular thalamus.
412 F. Giuliano, P. Clément / European Urology 48 (2005) 408–417
nections between those substructures and the medial
preoptic area (MPOA) of the hypothalamus, a brain
area known as essential in controlling sexual behaviour
[64], has been reported in anatomical and functional
studies [60,61].
The pivotal role of MPOA in ejaculation has been
documented in several experiments where both phases
of the ejaculatory process were abolished after MPOA
lesion [65] and elicited after chemical [66–68] or
electrical [68,69] stimulations of this hypothalamic
nucleus. Neuroanatomical studies failed to reveal the
existence of direct connections between the MPOA and
the spinal ejaculatory centres. However, it was shown
that MPOA projects to other brain regions involved in
ejaculation such as the paraventricular thalamic
nucleus (PVN) [70], the periaqueductal grey (PAG)
[71], and the paragigantocellular nucleus (nPGi) [72].
The PVN has long been known as a key site for
neuroendocrine and autonomic integration [73]. Par-
vocellular neurones of the PVN directly innervate
autonomic preganglionic neurones in the lumbosacral
spinal cord [74,75] and pudendal motoneurones
located in the L5-L6 spinal segment in rats [47].
PVN also sends direct projection to nPGi in the brain-
stem [76]. Bilateral chemical lesion of the PVN with
NMDA was associated with a one third reduction in the
weight of the seminal material ejaculated [77]. Retro-
grade and antegrade tracing studies have shown that
SPFp sends projections to BNST, MeA, and MPOA
[78,79] and receives inputs from LSt cells [55]. These
data suggest a pivotal role for SPFp although functional
investigations are lacking. The other forebrain struc-
tures which have been proposed, based on c-Fos pattern
of expression, to take part in regulation of the ejacu-
latory process in rat are MeA, BNST, and PNpd
[59,61]. Their precise roles remain unclear but they
may be involved in the relay of genital sensory signals
to the MPOA.
In the brainstem, nPGi and PAG have received
increasing attention. A strong inhibitory role of nPGi,
which projects to cellular bodies of pelvic efferents and
interneurones in the lumbosacral spinal cord [80,81],
on ejaculation in rats has been suggested from inves-
tigations using an experimental model, namely ure-
throgenital reflex, mimicking the expulsion phase of
ejaculation [81,82]. The same experimental paradigm
was used to demonstrate the important role of PAG [83]
in controlling the expulsion reflex. In addition, as
established in neuroanatomical studies, PAG constitu-
tes a relay between MPOA and nPGi [61,84]. Clearly,
midbrain structures exert a regulating function on
ejaculation but further investigations are required for
revealing the details of this regulation.
Recently, Holstege and colleagues [85] by using
positron emission tomography (PET) to investigate
increases in regional cerebral blood flow in human
during ejaculation and orgasm in humans, showed that
the strongest activation occurs in mesodiencephalic
transition zone including ventral tegmental area
(VTA), medial and ventral thalamus and SPFp.
4. Serotonergic control of ejaculation
The neurochemistry of ejaculation is a complex field
calling for additional studies. A number of neurotrans-
mitters, including serotonin (5-HT), dopamine, oxyto-
cin, GABA, adrenaline, acetylcholine and nitric oxide,
have been shown to be involved in the regulation of
ejaculation [36]. Amongst them, 5-HT intervening at
different levels of the neuraxis plays a primary role.
The data presented below have been obtained in rats.
4.1. Central serotonergic pathways and ejaculation
The 5-HT system is one of the most diffusively
organized projection systems of the brain. The majority
of the cell bodies of 5-HT neurones is located in the
brainstem at the level of the dorsal raphe and median
raphe nuclei. At the level of diencephalon, autoradio-
graphic and immunocytochemical studies have shown
the presence of 5-HT terminals within the hypothala-
mus (MPOA), MeA, BNST and PNpd [86,87].
On the other hand the spinal cord receives a strong
descending 5-HT innervation from the brain. Through-
out the grey matter there is a huge density of 5-HT
axons which form a rich network of fibres. Dense 5-HT
innervation exists in i) the dorsal horn, particularly
lamina I and to a lesser extent lamina II, ii) the motor
nuclei (laminae VII and IX) of the ventral horn and iii)
the intermediolateral column at the thoracic, lumbar
and sacral levels [88,89]. The origins of the 5-HT
projections to the dorsal horn are mainly the neurones
of the raphe magnus nucleus and reticular formation
[90]. The 5-HT axons innervating the ventral horn
originate from the raphe obscurus, raphe pallidus
nuclei and nPGi [80,81,91]. Immunohistochemical
studies have shown in male rats the presence of 5-
HT fibres in close vicinity of the dorsolateral (DL) and
dorsomedian (DM) motoneurones which innervate
bulbospongiosus and ischiocavernosus muscles respec-
tively [80,92]. Dense 5-HT immunoreactivity has also
been reported within the SPN [93].
Overall, the presence of 5-HT neurones and/or
terminals in brain structures involved in the control
of ejaculation such as MPOA, MeA, PNpd, BNST,
nPGi and in various areas i.e. dorsal horn, IML and
 F. Giuliano, P. Clément / European Urology 48 (2005) 408–417
ventral horn of relevant spinal segments provides a
strong anatomical support for a role of central 5-HT in
ejaculation.
4.2. Serotonergic receptors and ejaculation
5-HT receptors are highly heterogeneous and they
have been regrouped within seven different families (5-
HT1 to 5-HT7) [94]. Whereas all of the 5-HT receptor
subtypes are found postsynaptically, only 5-HT1A and
1B/D receptors are located presynaptically where they
mediate the negative feedback of 5-HT on its synaptic
release.
4.2.1. 5-HT1A receptors
Autoradiography, immunocytochemistry and in situ
hybridization techniques have shown the presence of 5-
HT1A somato-dendritic autoreceptors in the mesence-
phalic and medullary raphe nuclei [95].
At the spinal cord level, the highest densities of 5-
HT1A receptors are found in the dorsal horn (laminae
I-IV), SPN, and dorsal grey matter commissure (DGC)
at the lumbosacral levels [96–99]. The dense distribu-
tion of 5-HT1A receptors in the dorsal horn likely
indicates the involvement of these receptors in the
spinal processing of sensory information from the
periphery and conveying this information to the brain.
Accordingly, 5-HT1A receptors located in the dorsal
horn may also play a role in modulating the triggering
of ejaculation. The location of 5-HT1A receptors in the
intermediolateral nucleus (IML) of the lumbar and
sacral segments, indicate that these receptors may be
important in the regulation of both sympathetic and
preganglionic efferent activity [98,100]. In the ventral
horn, binding for 5-HT1A receptors agonists has been
reported in the dorsolateral (DL) nucleus of the puden-
dal nerve [97,99] that innervates the ischiocavernosus
muscles in rats.
4.2.2. 5-HT1B receptors
In contrast to 5-HT1A receptors which have soma-
todendritic position on 5-HT neurones, the 5-HT1B
receptors are located on terminals of 5-HT cells and
play a role as autoreceptors controlling 5-HT release in
the synaptic cleft. It has been demonstrated that selec-
tive 5-HT1B antagonists might prevent 5-HT negative
feedback via this site, increasing extraneuronal 5-HT.
Several investigators have demonstrated the presence
of 5-HT1B receptors in the spinal cord also located on
5-HT terminals [101–103]. Autoradiography, immu-
nohistochemistry and in situ hybridization studies have
detected a moderate and low density of 5-HT1B
receptors in the hypothalamus. In the spinal cord a
high density of 5-HT1B receptors was detected in
413
dorsal horn especially in lamina III, IV, in the dorsal
grey commissure surrounding the central canal and in
SPN at the lumbosacral level [103,104]. At the lumbar
level, the intermediolateral nucleus present high den-
sity of 5-HT1B receptors [103,104]. In the ventral horn,
DL and DM nuclei also contain high density of 5-
HT1B receptors [104].
4.2.3. 5-HT2C receptors
Autoradiography and in situ hybridization studies
have demonstrated the abundance of 5-HT2C receptors
in the hypothalamus [105]. In the spinal cord, radi-
oligand binding and in situ hybridization techniques
provided evidence for the presence, at low concentra-
tion, of 5-HT2C receptors at the lumbosacral level
[104,106]. Recently, high density of 5-HT2C receptors
has been visualized in ventral horn motoneurones and
in neurones of the SPN and the DGC in the lumbosacral
spinal cord [76].
4.3. Functional role of 5-HT in the control of
ejaculation
4.3.1. Central site of action
A great body of evidences indicates that the overall
effect of 5-HT on ejaculation is inhibitory [107,108].
The role of 5-HTand the 5-HT system on sexual reflexes
was investigated using the urethrogenital (UG) reflex
paradigm, an experimental model developed in anaes-
thetised rats by McKenna’s group and considered as a
spinal expulsion-like reflex [32]. As a conclusion of
several series of experiments, it was suggested that 5-HT
released at L3-L5 spinal segments from terminals of
axons descending from the rostral region of the nPGi
exerts an inhibitory role on ejaculation [81,82]. The
inhibitory influence of 5-HT projections originating in
nPGi and terminating in lumbosacral segments was
further supported in a more recent study using another
experimental paradigm also mimicking the ejaculatory
reflex [109].
Cerebral sites of action for 5-HT to exert its inhi-
bitory effect on ejaculation have been evidenced in a
number of behavioural studies [110–112]. Indeed,
microinjection of 5-HT into rat MPOA resulted in
prolongation of the ejaculation latency. In addition,
the local application of 5-HT in serotonergic projection
field within the forebrain induced a delay of ejaculation
[111]. Conversely, facilitation of male rat ejaculatory
behaviour was reported after delivery of 5-HT onto
raphe nuclei containing serotonergic cell bodies [113].
4.3.2. Role of 5-HT1A receptors (Table 1)
Facilitator effect of 8-OH-DPAT, a selective agonist
of 5-HT1A receptors, on ejaculation has been evi-
414 F. Giuliano, P. Clément / European Urology 48 (2005) 408–417
Table 1
Localisation and effect of stimulation of the different 5-HT receptor subtypes shown involved in ejaculation
5-HT receptor subtypes Tissular location
5-HT1A Brain (MRN, Accumb.)
Spinal (DH, DGC, DL, IML, SPN)
5-HT1B Brain (Hypothalamus)
Spinal (DH, DGC, DL, DM, IML, SPN,)
5-HT2C Brain (Hypothalamus)
Spinal (DGC, SPN)
Abbreviations: Accumb., nucleus accumbens; DGC, dorsal grey commissure; DH, dorsal horn; DL, dorsolateral nucleus; DM, dorsomedial nucleus; IML,
intermediolateral nucleus; MRN, median raphe nucleus; SPN, spinal parasympathetic nucleus.
denced by decreasing the number of intromissions
before ejaculation and the ejaculation latency in rats
after systemic delivery [114,115]. This pro-ejaculatory
effect was observed after microinjection of 8-OH-DPAT
in brain areas such as median raphe nucleus or nucleus
accumbens [111,112]. Consistent with the findings that
5-HT in general inhibits ejaculation, 8-OH-DPAT likely
blocks this inhibitory effect by decreasing the release of
5-HT in the synaptic cleft. In this favour, stimulation of
5-HT1A autoreceptors located on 5-HT cell bodies in
the raphe nuclei by microinjection of 8-OH-DPAT,
decreased 5-HT cell firing and consequently 5-HT
terminal release [116,117].
4.3.3. Role of 5-HT1B receptors (Table 1)
It has been shown in several studies that subcuta-
neous administration of the 5-HT1B receptor agonists
(anpirtoline, TFMPP) impaired ejaculation in rats
[112,114]. Further investigations reported that the 5-
hydroxytryptophan (5-HTP)-induced inhibition of
male rat ejaculatory behaviour was antagonized by
cotreatment with 5-HT1B receptor antagonist isomol-
tane [118]. As at the spinal level 5-HT1B receptors are
postsynaptically expressed on motoneurones in DL and
DM nuclei, these receptors may mediate the inhibitory
effect of 5-HT on ejaculation.
4.3.4. Role of 5-HT2C receptors (Table 1)
There are very few experimental evidences in favour
of a role of 5-HT2C receptors in ejaculation. Systemic
acute administration of 5-HT2C agonist DOI has been
shown to suppress ejaculation in rats [119]. In these
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