Dopamine and sexual function

Abstract

The use of the D1/D2 dopamine receptor agonist apomorphine SL for the treatment of erectile dysfunction provides a strong support in favour of a participation of the dopaminergic system in the control of sexual function. However, the exact involvement of dopamine in sexual motivation and in the control of genital arousal in humans is unknown. In contrast, experimental data suggest an implication of dopamine at all these stages of the copulatory behaviour in rodents. The release of dopamine at the level of the nucleus accumbens, which is innervated by the mesolimbic dopaminergic pathway originating in the ventral tegmental area, is positively implicated in the pre-copulatory or appetitive phase in male rats. There is also a permissive role in the copulatory or consumatory phase for dopamine released at the level of the median pre-optic area, which receives projection from the dopaminergic incertohypothalamic pathway within the hypothalamus. It is noteworthy that these participations of the dopaminergic system are not specific to sexual behaviour but rather reflect the more general involvement of dopamine in the regulation of cognitive, integrative and reward processes. Due to its role in the control of locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory behaviour. Somehow more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal cord. The counterpart of such regulation of the genital arousal by dopamine has not yet been established in females. In conclusion, the central dopaminergic system is a key element of the control of sexual function.

Full text

Dopamine and sexual function
F Giuliano
1,2
* and J Allard
2
1
Groupe de Recherche en Urologie, UPRES, Medical University of Paris South, France; and
2
PELVIPHARM Laboratories,
Domaine INRA, France
The use of the D
1
=D
2
dopamine receptor agonist apomorphine SL for the treatment of erectile
dysfunction provides a strong support in favour of a participation of the dopaminergic system in
the control of sexual function. However, the exact involvement of dopamine in sexual motivation
and in the control of genital arousal in humans is unknown. In contrast, experimental data suggest
an implication of dopamine at all these stages of the copulatory behaviour in rodents. The release
of dopamine at the level of the nucleus accumbens, which is innervated by the mesolimbic
dopaminergic pathway originating in the ventral tegmental area, is positively implicated in the
pre-copulatory or appetitive phase in male rats. There is also a permissive role in the copulatory
or consumatory phase for dopamine released at the level of the median pre-optic area, which
receives projection from the dopaminergic incertohypothalamic pathway within the hypothala-
mus. It is noteworthy that these participations of the dopaminergic system are not specific to
sexual behaviour but rather reflect the more general involvement of dopamine in the regulation of
cognitive, integrative and reward processes. Due to its role in the control of locomotor activity, the
integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory
behaviour. Somehow more specific to sexual function, it is likely that dopamine can trigger penile
erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the
hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal
cord. The counterpart of such regulation of the genital arousal by dopamine has not yet been
established in females. In conclusion, the central dopaminergic system is a key element of the
control of sexual function. International Journal of Impotence Research (2001) 13, Suppl 3, S18–
S28.
Keywords: apomorphine SL; central control; nucleus accumbens; Uprima
1
Introduction
Penile erection is one component of a complex
series of integrated physiological processes that
encompass male sexual behaviour. Erection is a
vascular event associated with tumescence of the
cavernous bodies that relies upon integration of
neural and humoral mechanisms at various levels in
the neuroaxis. It is unique among visceral functions
in that there is an absolute requirement for central
neural input to ensure proper function; any pertur-
bation of neural pathways can produce erectile
dysfunction. Thus, the central nervous system
(CNS) would be an extremely attractive target for
any novel therapeutants.
1
Multiple potential sites have been identified in
the CNS for active erectogenic drugs, based on
modulation of neurotransmission within the synap-
tic cleft. From the perspective of the pharmaceutical
industry, one of the most viable options is to attempt
to mimic the actions of one of the key neurotrans-
mitters. One such major neurotransmitter funda-
mentally involved in central processing of the
integrated erectile response is dopamine.
Within the CNS, the master organ is the brain,
which sends both activatory and inhibitory projec-
tions on the spinal centres driving the sexual
organs.
2
To provide the overall co-ordinated control
of the autonomic nervous system the brain utilises
one of two broad anatomical strategies (Figure 1).
These rely on either a hierarchical or a diffuse
distribution of neural interconnections. Operating
within these systems are several major neurotrans-
mitters. Those neurotransmitters particularly rele-
vant for the control of sexual function at the level of
the (CNS) are serotonin (5-HT), norepinephrine,
oxytocin, nitric oxide (NO) and dopamine (DA).
3,4
Historically, the pro-sexual effect of DA in humans
were first suggested by the observation of increased
sexual activity in Parkinson’s patient treated with
DA agonists such as L-DOPA, the endogenous
precursor of DA, although the incidence of such
symptoms were very rare.
5,6
Subsequently, several
*Correspondence: F Giuliano, Dept of Urology, CHU de
Bice
ˆtre, 78 rue du Ge
´ne
´ral Leclerc, 94270 Le Kremlin Bice
ˆtre,
Cedex, France.
E-mail: giuliano@cyber-sante.org
International Journal of Impotence Research (2001) 13, Suppl 3, S18–S28
ß2001 Nature Publishing Group All rights reserved 0955
-
9930/01 $15.00
www.nature.com/ijir

reports confirmed the ability of L-DOPA to induce
erections.
7–9
In one study, the ergot alkaloid
bromocriptine, a reasonably selective D
2
agonist at
the D
2
receptor subtype restored sexual functions in
male hemodialysis patients.
10
Paradoxically, how-
ever, in early studies in patients suffering from
erectile dysfunction (ED) of various aetiologies,
bromocriptine was found to be of limited value in
the treatment of male impotence unless hyperpro-
lactinaemia was a component of the disease.
11,12
The literature on DA receptor antagonists eg the
neuroleptics is ambiguous. They have been reported
to both impair erections and yet also to produce
prolonged erection.
13 – 15
However, several pilot studies have unambigu-
ously demonstrated that the semi-synthetic DA
D
1
=D
2
receptor agonist, apomorphine, could induce
penile erections in healthy men and in men with
ED.
16 – 18
Overall, until the recent large-scale clinical
trials on apomorphine, the link between sexual
function and DA in man was tenuous. In contrast,
numerous pharmacological studies have established
a fundamental role for DA in the control of sexual
function in both male and female rodents (for an
extensive review see reference.
19
) To help under-
stand the clinical profile of apomorphine the animal
data are described below.
DA synthesis, metabolism and receptors
The catecholamine family is constituted by DA,
together with norepinephrine and epinephrine.
With serotonin and histamine, they represent the
main amines within the CNS. DA is synthesised
from tyrosine in a two step reaction, involving first
tyrosine hydroxylase (generating 3.4-dihydroxy-L-
phenylalanine or L-DOPA) and second DOPA
decarboxylase, generating DA. Conversion of tyro-
sine to L-DOPA and L-DOPA to DA occurs in the
cytosol; DA is then taken up into storage vesicles.
After release in the synaptic cleft, DA is actively
taken back up from the extracellular space by
specific transporters. In humans, the catabolic
inactivation of DA is ensured principally (but not
exclusively) by monoamine oxidase MAO A (as
opposed to B) and catechol-o-methyl transferase (a
comprehensive review is given in reference
20
). The
alternative pathways for dopamine metabolism are
presented on Figure 2.
Dopamine receptors are members of the G-protein
coupled family with seven transmembrane protein
domains (Figure 3).
Five DA receptors have been cloned. D
1
-like
receptors (D
1
and D
5
) are stimulatory and are
coupled to adenylate cyclase and D
2
-like receptors
Figure 1 Schematic drawing of the hierarchical control of sexual reflexes. Higher sensory inputs are integrated with hormonal inputs in
the medical pre-optic area (MPOA), which then relays information through the brainstem to the spinal cord. The brainstem inputs onto
the spinal cord circuits regulating sexual reflexes are primarily inhibitor. Neurons in the nucleus paragigantocellularis (nPGi) control this
inhibition. Excitatory pathways may relay through the midbrain periaqueductal grey (PAG) to the spinal cord or via dis-inhibition of
nPGi neurons. Genital stimulation can initiate motor output by activating spinal cord systems directly. Sympathetic, parasympathetic
and somatic systems are interconnected by spinal interneurones that regulate spinal motor output.
Dopamine and sexual function
F Giuliano and J Allard
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International Journal of Impotence Research

(D
2
,D
3
and D
4
) are inhibitory or not coupled to this
enzyme. The pharmacology, molecular biology and
the anatomical localisation of the dopamine receptor
family are shown in Table 1. D
1
receptors are
adenylate cyclase stimulating (G
s
protein complex),
whereas D
2
receptors are adenylate cyclase inhibit-
ing (G
1
protein complex).
DA is implicated in a wide range of physiological
functions. For example, in Parkinson’s disease,
which is characterised by a degeneration of the
nigrostriatal DA tract, there is a dramatic loss in the
control of motor activity (for review see reference
21
).
On the other hand, neuroleptics, which are often
effective in blocking hallucinations and delusions in
schizophrenia, share the common property to be DA
antagonists (for review see reference
22
). Thus, DA is
involved in the control of motor activity in the
striatum but also in cognitive, emotional and reward
processes in the limbic area. In this line, it has been
proposed that DA neurons do not have specific
functions but rather regulate and enable integrative
functions in the neuronal system onto which they
project.
23
Figure 4 represents a schematic diagram of
the dopaminergic tracts in the rat brain and spinal
cord discussed in this report.
Dopamine o-Methyldopamine
AR
AD
AR
AD
DOPAC Homovanillic acid
MAO MAO
Figure 2 Alternative pathways of dopamine metabolism. (COMT) catechol O-methyltransferase; (MAO) monoamine oxidase; (AD)
aldehyde dehydrogenase; (AR) aldehyde reductase (alcohol dehydrogenase); (DOPAC) 3.4-dihydroxyphenylacetic acid. Reproduced
from reference.
21
Dopamine Receptor
Figure 3 Schematic representation of the dopamine receptor
complex.
Dopamine and sexual function
F Giuliano and J Allard
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International Journal of Impotence Research

Involvement of DA in the ex copula control of
penile erection
An ex copula experiment is performed in the
absence of a sexual partner. As such, in males,
experiments ex copula demonstrate the ability of a
given compound to induce genital arousal (ie penile
erection) without sexual stimuli. In this situation,
the sexual motivation of the male rat, and hence its
level of sexual arousal, is dependent on the
receptive and proceptive behaviour of the female,
which is a variable parameter.
The paraventricular nucleus (PVN) and penile
erection
The PVN of the hypothalamus is richly innervated
by DA neurons that belong to the incertohypotha-
lamic system that in turn constitute part of the
intrinsic DA innervation of the hypothalamus.
24,25
The incertohypothalamic system is constituted by
the A13 group in the rostral region of the medial
zona incerta and the A14 group in the rostral
periventricular nucleus. The incertohypothala-
mic system innervates various regions within the
Table 1 Characteristics of dopaminergic receptors from molecular biology
D
1
-like D
2
-like
D
1
D
5
=D
1b
D
2
(Short)=(long)*** D
3
D
4
Amino acids 446 (h, r)* 477 (h) 414=443 (h) 400 (h) 387 (h)
475 (r) 415=444 (r) 446 (r) 368 (r)
Pharmacological characteristics
(K
d
, nM)**
SCH23390 (0.35)
Dopamine (2340)
SCH23390 (0.30)
Dopamine (228)
Spiperone (0.05)
Raclopride (1.8)
Spiperone (0.61)
Raclopride (3.5)
Spiperone (0.05)
Raclopride (237)
Clozapine (56) Clozapine (180) Clozapine (9)
Dopamine (1705) Dopamine (27) Dopamine (450)
Homology (%)
With D
1
receptor 100 82 44 44 42
With D
2
(short) 44 49 100 76 54
Receptor localisation Caudate=putamen Hippocampus Caudate=putamen Nucleus accumbens Frontal cortex
Nucleus accumbens Hypothalamus Nucleus accumbens Olfactory tubercle Midbrain, amygdala
Olfactory tubercle Olfactory tubercle Islands of calleja medulla (all low)
Frontal cortex Cerebral cortex (low) Cerebral cortex (low) Cardiovascular
system
Retina
*h ¼human, r ¼recombinant, **from radioligand binding studies, ***two forms identified defined on relative amino sequence length.
Figure 4 Anatomical representation of the major dopaminergic pathways involved in the regulation of sexual function in the rat.
Dopamine and sexual function
F Giuliano and J Allard
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International Journal of Impotence Research

hypothalamus, and notably the medial pre-optic
area (MPOA) in addition to the PVN.
Injection of doses of apomorphine as low as 5 ng
in the PVN can induce penile erections in freely
moving rat without the presence of a female.
26
Similar responses are obtained when the selective
D
2
agonist LY171555 is injected in place of apomor-
phine, but not with the D
1
agonist SKF38393.
26
Erections induced by direct central apomorphine
injection into the PVN are abolished by systemic
pre-treatment with the central D
1
antagonist,
SCH23390, or the D
2
antagonist, sulpiride.
26
In
anaesthetised rats, penile erections induced by
peripheral delivery of apomorphine are antagonised
by a preceding injection in the PVN of the D
1
receptor antagonist, SCH23390 or the D
2
antagonist,
sulpiride.
27
These experiments are consistent with
the pro-erectile action of apomorphine arising
primarily from activation of DA receptors localised
to the PVN. Consistent with this hypothesis is the
finding that apomorphine injection into other
hypothalamic structures, such as the ventromedial
and dorsomedial nucleus, the pre-optic area or the
nucleus accumbens did not induce penile erec-
tion.
26
The findings that in freely moving rats,
apomorphine-induced erections are abolished by
transection of the cavernous nerves
28
and are
inhibited by the central DA antagonist haloperidol,
whereas they are unaffected by the peripheral DA
antagonist domperidone
29
are all consistent with a
primary CNS action underlying the pro-sexual effect
of apomorphine. In addition, intracavernosal
injection of apomorphine failed to elicit penile
erection
27
ruling out a direct action within the
penile vasculature.
Overall, therefore, the pharmacology of the
response leaves no doubt that the activation of
neurons in the PVN can be considered as the sine
qua non for the pro-erectile effect of apomorphine to
occur, and this effect is mediated by DA D
1
and D
2
receptors. However, the link between DA and the
pathophysiology of ED is more tenuous. Measure-
ment of changes in DA release within the PVN
concomitant to penile erection during copulation
would be required to establish a link between
DA=PVN and the induction of penile erection.
Although, measurement of catecholamine turnover
in the PVN has been shown to be feasible in rats,
30
it
has not yet been performed before, during or after
copulation.
The PVN does not seem to be involved in the
control of reflexive erections, as erections elicited by
retraction of the penile sheath in restrained male
rats placed in a tube in a supine position were not
affected by apomorphine injected into the PVN.
31
On the other hand, apomorphine injections facili-
tated seminal emission during penile reflex.
31
This
was also the case when apomorphine was injected
into the PVN prior to copulation experiments,
although the dosing used (1 – 10 mg) was far above
the dosing necessary to induce penile erection.
32
The participation of the PVN in the control of
seminal emission is further supported by the ability
of electrical stimulations of the PVN to elicit the UG
reflex.
33
There is some limited data suggesting that the
central effects of apomorphine are mediated by
oxytocin and NO (Figure 5). There are oxytocinergic
projections from parvocellular neurons in the PVN
to the pro-erectile parasympathetic nucleus (SPN) in
the spinal cord.
34
As oxytocin delivered at the level
of the SPN induces penile erection in the anesthe-
tised rat, the network PVN-SPN might represent a
physiologic circuit involved in the generation of
penile erection.
35
PVN apomorphine-induced pe-
nile erections in the freely moving rat can be
antagonised by injection of an oxytocin antagonist
intracerebroventriculary, but not locally, directly
into the PVN.
36
It has been proposed that apomor-
phine-induced erections were mediated by the
activation of the hypothalamic-septo-hippocampal
oxytocinergic pathway. This proposal was based on:
(1) the ability of median septum lesions to prevent
the penile erection induced by apomorphine injec-
tion in the PVN; and (2) doses of apomorphine that
induced penile erection increased the concentration
of oxytocin in the hippocampus.
The role of NO in the CNS and in the central
control of erectile function and sexual behaviour is
not well documented. The inhibitor of NO synthase
L-NAME given intracerebroventricularly (i.c.v.) pre-
vented the occurrence of penile erection upon
systemic injection of apomorphine.
37
The concen-
tration of NO
27
in the PVN was increased by the
injection of apomorphine or the D
2
agonist
LY171555, which both induced penile erections.
Whereas an inhibitor of NO synthase, L-NAME,
inhibited both NO
27
and penile erection, oxytocin
antagonists injected i.c.v. did not prevent the
increase in NO
27
but did prevent the erectile
Figure 5 Schematic representation of the involvement of dopa-
minergic pathways in the control of erectile function in the rat.
Dopamine and sexual function
F Giuliano and J Allard
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International Journal of Impotence Research

responses. The authors inferred that DA agonists
induce penile erection and yawning by acting on D
2
receptors that increase NO synthase in the cell
bodies of the PVN projecting to extra-hypothalamic
areas.
Spinal cord and penile erection
Whereas the brain provided the overall integrated
control of sexual function, the sexual response is
ultimately controlled by spinal autonomic nuclei
(Figure 6).
3
Penile erection is caused by a change in the
activity of efferent autonomic pathways to the
erectile tissues ie a shift from an overall predomi-
nant sympathetic to parasympathetic outflow. The
cell bodies of these autonomic neurons are located
in the spinal cord at the thoracolumbar level for the
sympathetic nuclei and at the sacral level for the
parasympathetic nuclei (SPN).
The existence of DA projections from the A11 cell
group to the spinal cord as well as an intrinsic DA
innervation within the spinal cord raises the
possibility of an additional direct action of apomor-
phine at the spinal level.
38,39
Immunocytochemical
studies revealed that DA fibres and terminals exist
in virtually all laminae throughout the spinal
cord.
40,41
Furthermore, studies using ligand binding
techniques have shown the presence of D
1
and D
2
receptors in the spinal cord.
42
In male rats, D
2
receptors identified with immunochemistry and in
situ hybridisation have been located in the para-
sympathetic nucleus of the lumbosacral spinal cord,
which contains the cellular bodies of the pro-
erectile autonomic neurons innervating the penis.
43
D
2
receptors have also been found to be particularly
abundant in the dorsomedian and the dorso-
lateral nucleus which innervate bulbospongiosus
and ischiocavernosus striated muscles involved in
penile rigidity in the rat.
43
In agreement with these anatomical findings,
apomorphine delivered at the lumbosacral level
with an intrathecal catheter elicited erectile activity
in anesthetised rats.
44
In conscious rats, reflexive
erections are depressed by peripheral injection of
the non-specific DA agonist RDS-127 in normal and
spinalised rats, and by intrathecal (i.t.) injection of
apomorphine at the lumbosacral level.
45,46
These
results suggest that there may a spinal action for DA
in the control of erection in addition to the one in
the brain described above (the PVN and penile
erection).
Control of female sexual motivation by DA
Female rat sexual behaviour
A brief outline of some aspects of rat sexual
behaviour is necessary for the understanding of the
present report (for a review see reference
47
). In
classical copulation tests, or mating experiments, in
which a male rat is in the presence of a receptive
female, the male rat performs a succession of
mounts with and without intromission before
performing a mount with intromission and with
ejaculation. At the same time, the female displays
characteristic behaviours, such as a lordotic posture
during mounts (a reflexive behaviour hormonally
induced) and sequences of running away from
the male with a characteristic gait (hopping and
darting).
For the female, the lordosis quotient (number of
lordotic posture=number of mounts by the male)
reflects its receptivity. Lordosis can be considered as
a passive behaviour of sexual motivation, whereas
the hopping and darting sequences reflect its
proceptivity or active behaviour of sexual motiva-
tion. Some data are in favour of a control of the
female receptivity and proceptivity by DA.
Involvement of DA in female rat sexual motivation
Some studies showed that the lordotic response of
ovariectomised estrogen-treated rats was increased
by DA receptor blockers (such as sulpiride or
spiroperidol) while it was decreased by DA agonists
(such as apomorphine or piribedil).
48,49
On the other
Figure 6 Integrated erectile response involving spinal and
supraspinal pathways.
Dopamine and sexual function
F Giuliano and J Allard
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International Journal of Impotence Research

hand, apomorphine was found to be able to increase
the lordotic response of ovariectomised rats treated
with oestrogen and progesterone when given sys-
temically.
50
Stimulation of D
2
receptors by either
LY171555 or LY163502 was also found to increase
the lordotic response of low receptive ovariecto-
mised oestrogen treated rats.
51
D
2
agonists can also
increase proceptivity counts.
52
In contrast, selective
D
1
agonists and antagonists do not affect measures
of proceptivity and receptivity in female rats.
49,51
However injections in discrete brain areas can reveal
an effect of D
1
agonist=antagonist on lordosis. For
example, a D
1
receptor agonist, but not a D
2
receptor
agonist, infused i.c.v., mimicked the effects of
progesterone in facilitating sexual behaviours in
oestrogen primed, ovariectomised female rats.
53
A possible explanation to reconcile this discre-
pancy is that low doses of DA agonists facilitate the
lordotic responses in low receptive female rats,
while high doses decrease the lordotic response in
fully receptive female rats. However, it is note-
worthy that the sexual steroids oestrogen and
progesterone exert marked effects on the DA system.
Ovariectomy or steroid treatment have been re-
ported to induce changes in DA content and turn-
over
54,55
and in the density of DA receptors.
56,57
Experiments with neurochemical lesions of the
mesolimbic DA pathways with 6-hydroxydopamine
could not lead to straight conclusions. Some
experiments showed a facilitation of lordosis beha-
viour upon lesions,
58
while others found no effect
on either lordosis or proceptive behaviour.
59
Microdialysis experiments have shown that DA
levels in the MPOA rose at the time sexual
receptivity is initiated by hormonal priming in
females. In addition, there is a further increase in
DA release when the male and female rats are
allowed to copulate, but not when they are physi-
cally separated.
60
This is an argument for a physio-
logical role of DA in the appetitive phase of sexual
behaviour in female rats.
Control of male sexual motivation by DA
Results from classical mating experiments
For the male, the latency for the first intromission
can be considered as a parameter reflecting the
motivation of the male rat to copulate. DA agonists
systemically delivered such as apomorphine, bro-
mocriptine, pergolide or lisuride facilitates copula-
tion in males in the presence of receptive females
(decreased the intromission latency), and lowered
the ejaculatory threshold (decrease in intromission
number and ejaculation latency).
19
Results from classical copulatory experiments
support a positive involvement of DA in the nucleus
accumbens in the anticipatory phase of sexual
behaviour. The mesocortical=mesolimbic pathway
innervates the nucleus accumbens. The mesocorti-
cal=mesolimbic pathway is constituted by the DA
cell bodies that lie medial to the substantia nigra
(ventral tegmental area, A10). They provide a diffuse
innervation to the forebrain, including frontal and
cingulate cortex, septum, nucleus accumbens and
olfactory tubercle.
Injection of apomorphine in the nucleus accum-
bens decreased the latency to begin copulating in
copulatory experiments, but not when injected in
the septum or the striatum.
61
In agreement, D-
amphetamine, which induces release of DA from
nerve terminals, significantly decreased mount and
intromission latency when injected in the nucleus
accumbens, without affecting mount number and
ejaculation latency.
62,63
Conversely, injection of
apomorphine in the ventral segmental area in-
creased intromission latency, probably inhibiting
the mesolimbic DA pathway through stimulation of
autoreceptors, and thus decreasing DA transmission
at the level of the nucleus accumbens.
64
Necessity for alternative tests to the classical mating
experiment
In spite of these findings with DA agonists in mating
experiments, DA antagonists were found to have no
effect on intromission or ejaculation latencies when
injected in the nucleus accumbens in copulatory
experiments when paired with fully receptive
females.
62,65
In contrast, when females were treated
with flupenthixol that eliminated proceptive beha-
viour, the D
2
antagonist raclopride decreased the
mount and intromission latencies when injected in
the nucleus accumbens, but not in the dorsal
striatum.
62
This demonstrates that the appetitive
behaviour of the male rat also relies upon the
females behaviour, or in other words a fully sexy,
lubric and demonstrative female will overcome the
specific antagonistic effect of a given drug on the
anticipatory behaviour of the male rat. A corollary of
this finding is that the classical copulatory experi-
ment definitely does not allow complete discrimina-
tion of appetitive and consumatory behaviour.
Indeed, it is not well accepted that classical
studies in which the male and the female continu-
ously interact in one way or another do not allow the
appetitive, or incentive motivational, component of
sexual behaviour to be clearly studied indepen-
dently of the ability to copulate. The male rat is
continuously teased by the proceptive behaviour of
the female, and the female is also affected by the
exploratory behaviour of the male.
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F Giuliano and J Allard
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Control of sexual motivation in the nucleus
accumbens by DA
Specific tests have been developed to discriminate
the appetitive from the consumatory component of
sexual behaviour, such as the bilevel chambers. In
this test, the male rat chases the female from one
level to another after each intromission. The number
of level changes in a fixed time before the introduc-
tion of the female is considered a measure of the
anticipatory phase (or motivation) of sexual activity.
Such tests evidenced that DA plays a role in the
anticipatory or appetitive phase of the sexual
behaviour in male rats.
66
Using the bilevel chamber paradigm, it has been
shown that bilateral infusions of haloperidol (a
D
2
>D
1
antagonist) into the nucleus accumbens
reduced the anticipatory=preparatory phase of co-
pulatory behaviour but did not affect the consuma-
tory measures of copulation.
65
In contrast, infusion
of haloperidol in the MPOA reproduced all the
effects of systemic administration, ie decrease of
the anticipatory=preparatory and consumatory
phase of copulatory behaviour.
65
Such results
suggest a positive involvement of DA in the nucleus
accumbens in the anticipatory phase of sexual
behaviour.
DA measurement supports a physiological role of
DA in the nucleus accumbens in male rat sexual
behaviour. Extracellular DA increased in the nu-
cleus accumbens when an oestrous female was
presented behind a barrier, as well as during
copulation.
65
Exposure to a non-oestrous female
did not elicit DA release.
67
Thus, DA plays a
positive role in the anticipatory phase in male rats
at the level of the nucleus accumbens.
Control of sexual performance by DA
Medial pre-optic area (MPOA)
The MPOA is innervated by the incertohypothala-
mic pathway, which originates from the A14 group.
First, it is noteworthy that destruction of the MPOA
destroys male copulatory behaviour but not the
occurrence of spontaneous erection or penile erec-
tion upon penile reflex.
68
Instrumental measures of
sexual motivation were achieved by training males
to work for an oestrous female, presented in an
operant chamber under a second-order schedule of
reinforcement. MPOA lesions abolished mounts,
intromissions and ejaculation but did not disrupt
instrumental responses, investigation of the female,
or abortive mounting attempts.
69
Injection of apo-
morphine in the MPOA reproduced the facilitatory
effects seen on copulatory behaviour in intact rats,
70
ie decreased mount latency and increased number of
ejaculations of rats that copulate. We have already
mentioned that infusion of haloperidol in the MPOA
reproduced all the effects of systemic administration
of haloperidol, ie decrease of the anticipatory=
preparatory and consumatory phase of copulatory
behaviour.
65
These data indicate a preponderant role of the
MPOA in the performance of sexual behaviour,
although a role in sexual motivation cannot be
completely ruled out. The major efferent projections
of the MPOA are to hypothalamic, midbrain, and
brain stem nuclei that regulate autonomic or
somatomotor patterns and motivational state.
71
It
has been postulated that the MPOA removes the
tonic inhibition on these patterns and thereby
allows sensory stimuli to elicit a motor response.
The stimulatory role of DA in the medial preoptic
area in physiological conditions has been confirmed
as DA and DOPAC were shown to be increased
during the precopulatory phase and during copula-
tion, and lowered after ejaculation.
72
Note that the
increase in DA level in the MPOA during the
precopulatory phase underlines a potential role in
the anticipatory phase, in addition to its well-
established role on performance.
Thus, DA participates at the level of the MPOA in
the control of performance and may also affect
sexual motivation, although to a lesser extent or less
clear extent than the nucleus accumbens.
Striatum
The nigrostriatal pathway is the major DA tract. It
originates in the zona compacta of the substantia
nigra (A9) and sends axons that provide a dense
innervation to the caudate nucleus and putamen of
the striatum (nearly 80% of all the DA in the brain is
found in the corpus striatum). The nigrostriatal
system plays a key role in the initiation and control
of movement, as emphasised in Parkinson’s disease.
Apomorphine injected into the striatum was
without effect on copulation in male rats.
61
In the
bilevel chamber paradigm, high doses of systemic
haloperidol delayed or abolished level changing and
the initiation of copulation probably by impairing
motor performance by blocking DA receptors in the
striatum.
65
Bilateral infusions of haloperidol into
the striatum only increased the number of ejacula-
tions in the bilevel chamber paradigm, possibly
because the striatum is a rather large structure that
needs a considerable amount of drug to be fully
affected.
66
DA is released in the dorsal striatum only after
the male begins to copulate, suggesting that here, DA
levels reflect primarily motor activation, rather than
motivational aspects of copulation.
73
In contrast,
forced locomotion on a rotating drum, exposure to a
Dopamine and sexual function
F Giuliano and J Allard
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International Journal of Impotence Research

novel chamber, and exposure to sex odours did not
increase DA significantly in the striatum, although
both DOPAC and HVA increased significantly in
both regions during the locomotion test.
73
Thus,
there is some specificity in the release of DA in the
striatum during copulation.
In humans
The only direct argument supporting the involve-
ment of the DA system in human sexual function
comes from the extensive clinical efficacy of
apomorphine SL in ED patients.
74,75
However, the
extensive work described in this article in rodents,
lends support to the ‘DA theory’ of the control of
human sexual function. In addition, non-human
primate studies showed that apomorphine and
LY163502 are capable of facilitating sexual beha-
viour of male rhesus monkeys only in the presence
of a receptive female they could at least see and
smell.
76,77
Interestingly, no facilitator effect was
seen in the absence of females.
Highly innovative magnetic resonance imaging
(MRI) studies have given some insight into the brain
structures involved in sexual arousal induced by
apomorphine. In a study with six patients with a
history of psychogenic ED, it was shown that the
inferior temporal regions on the right, superior
prefrontal cortex and posterior parietal regions
bilaterally, and the thalamus, were specifically
activated upon sub-lingual administration of apo-
morphine.
78
In comparison, visually evoked sexual
arousal (without drug treatment) was characterised
by: bilateral activation of the inferior temporal
cortex, a visual association area; activation of the
right insula and right inferior frontal cortex, which
are two paralimbic areas relating highly processed
sensory information with motivational state; and
activation of the left anterior cingulate cortex,
another paralimbic area known to control autonomic
and neuroendocrine functions.
79
However, further
experimentation is required. In particular it would
be of value to determine to what extent apomor-
phine activates brain structures that are quiescent in
sexual arousal that occurs in the absence of drug
induction or facilitation.
It has been demonstrated in rats that the DA
system is involved to varying extends at all satges in
the control of the sexual function, from the appeti-
tive to the consummatory phase. It is probable that
this is also the case in humans. Thus, the prosexual
action of apomorphine is likely to be much more
complex than the simple triggering of penile erec-
tion. Nevertheless, in clinical trials with sub-lingual
apomorphine, there was no major effect on sexual
desire as measured by the IIEF questionnaire.
80
Paradoxically, however, apomorphine has been
shown to increase libido in psychiatric patients.
81
An effect of apomorphine on sexual desire would be
of special interest for the treatment of female sexual
dysfunction.
Conclusion
Penile erection is a complex behavioural response
that is dependent on the interaction of several
diverse humoral and neural events at various levels
of the neuroaxis. Existing therapies act mainly by
the production of localised vasodilation in the penis
by augmentation of the NO system or attenuation of
the counterbalancing sympathetic nervous system.
However, the CNS that initiates signalling to the
penis and integrates the overall response has a
prime role in the normal sexual response. Several
lines of evidence indicate that the central dopami-
nergic system has a major role in the control of
sexual function and normal erectile activity in both
animals and man. It is likely, at the level of the
hypothalamus, that these dopaminergic systems are
fundamentally involved in the production of the
normal integrated response that results in penile
erection. Apomorphine acts on DA receptors to
rectify abnormal pathophysiology in the ED patient
and thereby restore normal erectile function.
DA is particularly involved in the appetitive=
anticipatory phase of sexual behaviour in the
nucleus accumbens and in the consumatory phase
in the dorsal caudate-putamen. This is consistent
with the more general role of DA in emotion and
cognitive function in limbic areas and in the control
of movement in the striatum, respectively. In the
MPOA, DA plays a permissive role in the expression
of copulatory behaviour. Eventually, DA is probably
involved in the triggering of the erectile response at
the level of the PVN and possibly in the lumbosacral
spinal cord.
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