nb9610.

qxd 12/03/1999 10:07 AM Page 751

751

Neurobiology of sexual behavior

James G Pfaus
Recent advances in the neurobiology of sexual behavior have Figure 1
helped to refine our understanding of the neuroanatomical,
neuroendocrine and neurochemical systems that modulate
responses to sexual stimulation. Both appetitive and
consummatory sexual behaviors have been studied in several
laboratory species and in humans using traditional and novel
behavioral paradigms. New knowledge has emerged
concerning the role of hypothalamic, limbic and brainstem
structures, neuropeptides, brain monoamines and nitric oxide
in the control of partner preference, sexual desire, erection,
copulation, ejaculation, orgasm and sexual satiety. Brain
imaging of visually evoked sexual arousal in humans has also
been examined.

Addresses
Center for Studies in Behavioral Neurobiology, Department of
Psychology, Concordia University, 1455 de Maisonneuve Boulevard W,
Montréal, Québec H3G 1M8, Canada;
e-mail: pfaus@csbn.concordia.ca

Current Opinion in Neurobiology 1999, 9:751–758

0959-4388/99/$ — see front matter © 1999 Elsevier Science Ltd.

All rights reserved.

Abbreviations
8-OH-DPAT 8-hydroxy-2-n-propylaminotetralin
BNST bed nucleus of the stria terminalis
DA dopamine
ERKO deletion of the α form of the estrogen receptor
L-DOPA L-dihydroxyphenylalanine
MEApd posterior-dorsal nucleus of the medial amygdala
mPOA medial preoptic area
NCE noncontact erection
NMMA Ng-monomethyl-L-arginine acetate Proportional distribution by female type of (a) first mount,
NO nitric oxide (b) intromission, and (c) ejaculation during a triad mating test. Almond
THP 5 α-pregnan-3α-ol-20-one extract was used as the conditioned stimulus (CS+) and was applied
VMH ventro-medial hypothalamus to the necks and ano-genital regions of sexually receptive females
(A+E) in the paired-trained group. Almond extract was applied to these
regions of sexually nonreceptive females in the unpaired-trained group,
Introduction and to both receptive and nonreceptive females in the random-trained
group. E-alone females had distilled water applied to these regions.
Substantial progress has been made in elucidating the Other neutral odors (e.g. lemon) are equally effective in this training
neuroanatomical, neuroendocrine and neurochemical reg- procedure. The learning in the unpaired-trained group also affords an
ulation of appetitive and consummatory aspects of sexual opportunity to examine the development and expression of conditioned
behavior. This effort has been aided by the addition of inhibition of sexual behavior. From Kippin et al. [1••], and reproduced
with permission.
new behavioral paradigms, animal models of drug-
induced human sexual dysfunction, and correlative work
in humans, especially in the area of brain and hormonal
activation by sexual stimuli. This review, which is by no odor, despite copulating indiscriminately with both females
means complete, attempts to provide a framework for (Figure 1). This conditioned ejaculatory preference was
some of the exciting research findings that have appeared Pavlovian in nature, as males in random- and explicitly-
since August 1998. unpaired control groups did not show the preference. The
conditioned odor presented alone to males in their bedding
Behavioral paradigms induced Fos protein, a marker of neuronal activation, in
A ‘triad mating paradigm’ was introduced [1••] in which a several brain regions involved in odor processing and sexu-
single male rat is placed into an open field with two sexual- al behavior (Figures 2 and 3). In contrast, males in the
ly receptive female rats. Males trained previously to explicitly unpaired group (i.e. in which the odor was paired
associate a neutral odor (almond or lemon) with sexual with a sexually nonreceptive female) developed a condi-
activity ejaculated preferentially with females bearing that tioned inhibition of sexual behavior toward receptive
nb9610.qxd 12/03/1999 10:07 AM Page 752

752 Neurobiology of behaviour

Figure 2 Figure 3

A-A E-A A-E A-No Training group/odor exposure

A+E-trained/almond odor
A+E- or E-trained/estrous odor
mPOA E-trained/almond odor
A+E- or E-trained/no odor

50 Medial preoptic area

40

of Fos-IR cells
Mean number
NAcc *
30
20
10
LHyp 0

100 Nucleus accumbens core

Current Opinion in Neurobiology

of Fos-IR cells
Mean number
75 *
The ability of unconditioned estrous odors, or a conditioned odor 50
(almond) paired with copulation, to activate Fos protein within several
brain regions. A-A, Fos induction in males trained to associate almond 25
odor with copulation and given an almond odor on cotton; A-E, Fos
induction in males trained to associate almond odor with copulation and 0
given an estrous odor on cotton; A-No, Fos induction in males trained to
associate almond odor with copulation and given water (no odor) on 80 Lateral hypothalamic nucleus
cotton; E-A, Fos induction in males trained to copulate with unscented
of Fos-IR cells
Mean number

receptive females and given an almond odor on cotton; LHyp, lateral 60

hypothalamus; NAcc, nucleus accumbens; mPOA, medial preoptic area.
*
40

females bearing the odor, suggesting that this paradigm can
be used to study potential disinhibitory effects of drugs on
sexual behavior. Subsequent experiments have revealed
that both ejaculation and the post-ejaculatory refractory
period are necessary unconditioned stimuli for the devel-
opment of the ejaculatory preference, and that the
preference can be conditioned during the male’s first sexu-
al experience with a female. The neuroanatomical basis of
this conditioning is currently being examined.
Animal models of human sexual dysfunction
Antidepressant and antihypertensive medications in
humans are notorious for their sexual side effects, including
the disorders of sexual desire, arousal and orgasm. Sub-
chronic and chronic effects of fluoxetine (Prozac, Eli Lilley
Incorporated, Indianopolis, USA) have been examined in
sexually active female [2] and male [3•] rats. Daily fluoxe-
tine administration for one to three weeks reduced lordosis
quotients in gonadally intact females in estrus without alter-
ing vaginal cyclicity. A similar reduction in lordosis was
observed in ovariectomized females maintained on estrogen
and progesterone. However, fluoxetine did not alter the
preference of females to spend more time near a sexually
active male over another female. In males, four to six weeks
of daily fluoxetine treatment induced a progressive decline
in the number of ejaculations (Figure 4). This effect was
dose- and time-dependent. A short-term decline in anticipa-
tory sexual excitement (level-to-level movements in a
two-level testing chamber during the five-minute adapta-
tion period prior to the presentation of the female) was also
20
0
Current Opinion in Neurobiology
Comparison of the ability of an almond odor conditioned with copulation
or an unconditioned estrous odor to induce Fos protein in various brain
regions. Data are means + SEM. *P < 0.05 from unconditioned odor
group. A+E, E and A: see legends in Figures 1 and 2.
observed; however, tolerance accrued to this effect over
time. No effects were observed on the latency to initiate
copulation, or on the rate of intromissions during a test, sug-
gesting that chronic fluoxetine did not alter the ability of
males to achieve and maintain erection. A single administra-
tion of oxytocin was able to reverse the decline in
ejaculation produced by chronic fluoxetine (Figure 5).
Chronic effects of the antihypertensive drugs clonidine,
propranolol and captopril [4] and a new angiotensin antago-
nist, losartan [5] were also evaluated. In normotensive male
rats, 16 weeks of clonidine or propranolol disrupted the ini-
tiation and rate of copulation and decreased the ability of
males to ejaculate. In contrast, the same treatment with
captopril had only small effects on these measurements.
Lotran was tested in both spontaneously hypertensive rats
and normotensive Kyoto–Wistar rats. Up to 90 days of losar-
tan treatment produced only small increases in the mount
latency of spontaneously hypertensive rats, but not in the
normotensives. Together, these data suggest that captopril
or losartan may be better therapeutic options for patients
nb9610.qxd 12/03/1999 10:07 AM Page 753

Neurobiology of sexual behavior Pfaus 753

Figure 4 Figure 5

(a) 16 control
1 mg/kg
14 5 mg/kg
10 mg/kg

Level Change Frequency (count)

12

10

0
Fluoxetine (Late) Oxytocin No Oxytocin
Trial Block

(b)
control
3.5
* 1 mg/kg
* 5 mg/kg
10 mg/kg
3
Ejaculation Frequency (count)

2.5

(a) Anticipatory sexual excitement (level-to-level movements in a bilevel

chamber, and (b) number of ejaculations at baseline and during 2
different chronic fluoxetine treatments. Data are means ± SEM.
*P<0.05, **P<0.01, from controls. From Cantor et al. [3•], and
reproduced with permission.
1.5

0
because they produce only minor reduction in sexual func- Fluoxetine (Late) Oxytocin No Oxytocin
tion compared with clonidine or propranolol. Trial Block
Current Opinion in Neurobiology

Stimulation of sexual desire and arousal

Neural mechanisms associated with motivational aspects
of sexual behavior, including the stimulation of erection
and ejaculation in sexually active rats, or the stimulation of
copulation in sexually sluggish or naive rats, have been
examined. Several studies have refined our understanding
of the regulation of noncontact erections (NCEs) in male
rats, a homologue of psychogenic erection in humans that
is stimulated by sex odors from the female. In sexually
experienced, castrated male rats, NCEs were stimulated
by implants of testosterone or its 5α-reduced metabolite,
dihydrotestosterone, but not by implants of estradiol [6•].
The display of NCEs was impaired by infusions of
D(CH2)5Tyr(Me)2-orn8-vasotocin (Tyr, tyrosine, Me,
methyl, Orn, ornithine), an oxytocin receptor antagonist, or
L-NMMA, a competitive inhibitor of nitric oxide (NO)
Effect of oxytocin or saline (no oxytocin) on the (a) number of
conditioned level changes and (b) number of ejaculations displayed by
male rats treated with chronic fluoxetine. Late phase fluoxetine data are
included for comparison. Oxytocin and saline were administered in an
A-B-B-A design, and data are added over the two A and B time points.
*P<0.05 from late treatment with fluoxetine. From Cantor et al. [3•],
and reproduced with permission.
synthase, administered to the lateral ventricles [7•,8].
Infusions of L-arginine or morphine, but not the κ-opioid
receptor agonist, U-69593, to the paraventricular nucleus
of the hypothalamus reduced NCEs [8]. Both L-arginine
and morphine also reduce concentrations of NO in the
paraventricular nucleus, suggesting that NO actions in this
nb9610.qxd 12/03/1999 10:07 AM Page 754
754 Neurobiology of behaviour
region are important for the display of NCEs. L-NMMA
infused into the medial preoptic area (mPOA) of male rats
was able to increase the number of seminal emissions in an
ex copula test of ejaculatory reflexes [9•], further supporting
the idea that NO activity in the mPOA tonically inhibits
ejaculation by decreasing sympathetic tone.
Interestingly, administration of testosterone to castrated
male rats increases the number of NO synthase-labelled
neurons in the mPOA, indicating an increase in NO synthe-
sis [10••]. NO is capable of stimulating dopamine (DA)
release in the mPOA, which in turn stimulates penile erec-
tion. This mechanism may constitute one way in which
androgens stimulate sexual arousal. Finally, lesions of the lat-
eral paragigantocellular nucleus in the medulla, an important
site for the control of descending inhibition on reflexive erec-
tions and ejaculation, did not affect NCEs [11•], suggesting
that NCEs are stimulated by a separate neural system.
Treating male rats with D-amphetamine prior to their first
sexual experience facilitated the acquisition of baseline
rates of sexual behavior and augmented anticipatory sexual
excitement after sexual behavior had been acquired [12••].
Such treatment also resulted in augmented DA release in
the nucleus accumbens when a receptive female was
placed behind a screen, relative to nonsensitized controls
[13••]. These data reveal that behavioral sensitization to
psychomotor stimulant drugs such as amphetamine can
‘cross-sensitize’ to natural stimuli such as sexual incen-
tives. Sexual behavior has also been stimulated in sexually
sluggish or naive male rats by extracts of Turnera diffusa
(Damina) and Pfaffia paniculata (Brazilian ginseng), both of
which contain androgenic alkaloids and various stimulants
[14]. Extracts of another stimulant, Eurycoma longfolia Jack
(Catuaba), enhanced the ability of male rats to cross elec-
trified grids to copulate with a receptive female, decreased
their mount, intromission and ejaculation latencies, and
increased the total number of ejaculations after nine to 12
weeks of treatment [15].
Some animals possess ‘endogenous’ sexual inhibition. For
example, obese Zucker Fatty rats are notable for their
decreased fertility and inhibited ability to copulate.
Infusions of antisera against neuropeptide Y to the third
ventricle of these animals were found to stimulate sexual
activity but also to decrease feeding and weight gain [16].
Male rats that have copulated to sexual exhaustion are also
notoriously poor copulators the following day. This long-
term inhibition of sexual behavior can be delayed by
changing the stimulus female [17•], or reversed by a com-
bination of the nonspecific DA receptor agonist
apomorphine and the α2 adrenergic receptor antagonist
yohimbine [18]. The opioid antagonist naloxone was also
able to stimulate copulation in sexually naive or castrated,
testosterone-replaced Japanese quail [19].
Appetitive sexual behavior in Japanese quail, such as con-
ditioned social proximity, requires copulation for its
development [20••], much like olfactory-conditioned ejac-
ulatory preferences do in rats [1••]. The display of both
appetitive and consummatory sexual behavior in castrated
quail can be stimulated by testosterone implants to the
mPOA [20••]. Lesions of the mPOA abolished copulatory
behavior and decreased appetitive sexual behaviors in
male quail, whereas lesions of the bed nucleus of the stria
terminalis (BNST) decreased copulatory behaviors only
[21••]. A microstructural analysis revealed that lesions to
the subdivision of the mPOA just rostral to the anterior
comissure impaired copulation, whereas lesions more ros-
tral to this subdivision impaired appetitive sexual
behaviors. These data suggest that androgen-sensitive,
aromatase-containing subregions of the mPOA may control
appetitive and consummatory sexual behaviors indepen-
dently. Estradiol stimulated genital investigation and
mounting of receptive females in castrated male rats with-
in 35 min of systemic injection, indicating a rapid, and
presumably nontranscriptional, effect of estradiol in these
aspects of sexual desire [22•]. Finally, androgens are able to
stimulate mounting in castrated male hamsters by place-
ment in either the mPOA or medial amygdala. However,
dual placement in both regions did not amplify the effect
of either placement alone, suggesting that these regions
contain redundant mechanisms [23•]. Although the activa-
tion of hormone-sensitive neurons in different brain
regions alone may not amplify the activation of copulatory
behavior, they enhanced the ability of chemosensory cues
to stimulate sexual behavior. Olfactory bulbectomy ispilat-
eral to an intracranial implant of testosterone prevented
any interaction of odors and androgens, and eliminated the
ability of androgens to stimulate mounting [24].
Copulation and sexual stimulation
Specific effects of drugs and hormones on consummatory
measures of copulation continue to be an important focus
of research, as do studies that reveal neuroanatomical acti-
vation following particular types of sexual stimulation.
Serotonin (5-HT) systems have been examined, with par-
ticular regard to the facilitation of ejaculation produced by
the 5-HT1A agonist 8-OH-DPAT. Interactions with DA
systems have been examined both in the mPOA [25] and
systemically [26]. Regarding female sexual behavior, the
inhibitory effect of 5-HT in the ventro-medial hypothala-
mus (VMH) on lordosis involves an integrated action of at
least three 5-HT receptor subtypes in this region [27].
Finally, DA-depleted female Drosophila melanogaster flies
showed dramatic decreases in sexual receptivity, despite
male flies maintaining their attraction to the females [28•].
This decrease in receptive behavior was reversed with the
addition of the DA precursor L-DOPA.
Continuing work by Frye and colleagues has shed new light
on the activation of sexual desire, proceptivity and receptiv-
ity in the female rat by progesterone and its neurosteroid
metabolite, 3α,5α-THP [29•]. These steroids rapidly acti-
vate sexual proceptivity and receptivity when infused to the
nb9610.qxd 12/03/1999 10:07 AM Page 755
ventral tegmental area of the midbrain, but not to be VMH
(in which progesterone’s ability to facilitate proceptive and
receptive sexual behavior requires protein synthetic changes
associated with the activation of intracellular progestin
receptors). The rapid actions of these neurosteroids most
likely reflects interactions with GABA/benzodiazepine
receptors, and the most recent study by these authors
extended this to the activation of partner preference.
Systemic administration of finasteride, an inhibitor of prog-
esterone metabolism into 3α,5α-THP, reduced partner
preference for a sexually vigorous male, and reduced rates of
proceptive behavior and lordosis quotients. Whole brain lev-
els of 3α,5α-THP were increased, whereas levels of
progesterone were decreased, in females allowed to pace
their sexual contact with males. Because previous studies
have shown that the ability to pace is necessary for females
to show sexually conditioned place preference, progesterone
and its neurosteroid metabolites appear to have important
actions on sexual motivation and reward in female rats.
Hormonal actions have also been examined in the induc-
tion of solicitation and pacing behavior in female rats.
Solicitation in bilevel chambers was induced by estrogen
and progesterone, but not by estrogen alone [30]. Pacing,
which causes intromissions to be distributed in time, was
induced by estrogen in bilevel chambers and also in cham-
bers in which the female could escape the male through a
small hole [30,31]. However, progesterone did not appear
to increase rates of pacing behavior above that observed
with estrogen alone [31]. The display of sexual receptivity
in female rodents declines over a period of hours, an effect
that is enhanced if the females receive paced intromissions
by a male. Infusions of the protein synthesis inhibitor ani-
somycin to the mPOA of female hamsters prevented the
ability of intromissions to advance the termination of
estrus, indicating that vagino-cervical stimulation-induced
activation of the mPOA regulates estrus termination [32••].
Induction of Fos protein in neurons following sexual stimu-
lation continues to be used to trace functional pathways in
the brain. Equivalent increases in Fos have been found in
the brains of both juvenile and adult male hamsters follow-
ing exposure to female hamster vaginal secretions [33•].
Activated regions included the posterior-medial BNST, the
medial nucleus of the mPOA and the posterior-dorsal nucle-
us of the medial amygdala (MEApd). Male rats that display
NCEs in response to distal cues from females show signifi-
cantly increased Fos induction in the nucleus accumbens,
MEApd, BNST and mPOA, compared with males that do
not [34•]. In adult males that copulate to sexual exhaustion,
an increased amount of Fos was found in the caudal MEApd
and posterior-medial and ventral nuclei of the BNST com-
pared with males that achieved a single ejaculation [35••],
suggesting that subregions of these sites may be involved in
the inhibition of sexual behavior. Fos induction in the
mPOA following copulation also appears to increase as
males become more sexually experienced [36••], an effect
that depends on stimulation of D1 receptors.
Neurobiology of sexual behavior Pfaus 755
Studies using double immunocytochemistry with antero-
grade and retrograde tracers in conjunction with
copulation-induced Fos has revealed sites that send and
receive information to and from the mPOA [37•]. Sites
with bidirectional connections include the posterior-medi-
al BNST, the posterior-dorsal nucleus of the anterior
hypothalamus, MEApd, and the posterior subparafascicu-
lar nucleus. Each of these regions has been shown
previously to be activated by both intromissive and ejacu-
latory stimulation. Although copulation-induced Fos is not
colocalized with aromatase in the mPOA of male Japanese
quail [38], it is colocalized with androgen receptor in the
mPOA, BNST, lateral hypothalamus, VMH, central amyg-
dala, and SPFp of male rats [39•].
Finally, several studies have used mice with particular gene
knockouts to reveal the hormonal control of sexual behav-
ior. Progesterone was found to facilitate lordosis in females
with a deletion of the progesterone receptor [40•], suggest-
ing that progesterone may act on substrates other than the
intracellular progestin receptor to facilitate lordosis.
Consistent with previous work in rats by these authors,
such substrates may involve rapid membrane effects of
progesterone on GABA/benzodiazepine receptor complex-
es. Female mice with a deletion of the α form of the
estrogen receptor (ERKO) did not display lordosis follow-
ing hormone treatment, but instead were highly aggressive
toward males that attempted to mount them [41•]. In con-
trast, ERKO males lacked offensive aggression compared
with wild-type males [42•], but both testosterone and dihy-
drotestosterone were capable of restoring mounting
behavior. ERKO males were as likely as ERKO females to
show infanticide, however. Although these results suggest
that the α form of the estrogen receptor is not necessary for
the stimulation of male sexual behavior by androgens in
mice, male mice with a deletion of the aromatase gene had
longer latencies to initiate sexual activity [43•].
Human sexual behavior
Several advances have been made in understanding the
relationship between plasma hormone levels and sexual
desire, arousal and stimulation. Monthly measures of sali-
vary testosterone were correlated positively with the
initiation and rate of sexual intercourse in adolescent males
[44•]. In aging males, however, the androgen dihy-
droepiandrosterone (DHEA), much publicized for its ability
to improve sexual function and general sense of well-being,
had only transient effects in a well-controlled, double-blind
study [45]. However, mixed estrogen/androgen replacement
to postmenopausal women improved measures of sexual
desire, satisfaction and frequency of sexual activity, com-
pared with treatment with estrogen alone [46•].
Neuroendocrine correlates of sexual stimulation were also
assessed following orgasm. In both men and women,
orgasm induced by masturbation increased heart rate,
blood pressure and plasma levels of noradrenaline tran-
siently (all indices of increased sympathetic activation),
nb9610.qxd 12/03/1999 10:07 AM Page 756
756 Neurobiology of behaviour
but also increased plasma levels of prolactin consistently
for 30 min in men and 60 min in women [47••,48••]. In
women, sexual arousal increased plasma levels of luteiniz-
ing hormone and testosterone [48••]. In another study,
plasma oxytocin levels were also increased in women fol-
lowing orgasm [49].
The first study of neuroanatomical activation in human
brains following visually evoked sexual arousal has been
published [50••]. Positron emission tomography was used
to identify activation in human males following exposure
to sexually explicit, humorous or emotionally neutral film
clips. Sexual arousal was associated with bilateral activa-
tion of the inferior temporal cortex, the right insular and
inferior frontal cortex and the left anterior cingulate cortex.
The latter two regions are considered paralimbic, and play
a role in processing sensory information related to motiva-
tion and autonomic functions. The degree of activation in
these regions also correlated positively with plasma testos-
terone concentrations.
Conclusions
The introduction of Viagra (Pfizer, UK) in 1998 marked a
resurgence of interest in the neurobiology of sexual function
and dysfunction. Thanks to years of progress in understand-
ing basic brain, hormonal and neurochemical mechanisms of
copulatory behavior, and recent advances in molecular biolo-
gy and pharmacology, we stand at a crossroads in the study of
sexual behavior. Trends in the past year indicate that more
appetitive aspects of sexual desire and arousal are being stud-
ied in laboratory animals and humans. New behavioral
paradigms are being introduced, and neuroanatomical, neu-
roendocrine and neurochemical correlates of sexual
stimulation within these paradigms are being assessed. This
information is likely to be of enormous help to clinicians in
testing medications with potential sexual side-effects. The
use of brain imaging in humans is especially exciting, and the
inclusion of other methods of assessing brain activation in
real time (e.g. functional magnetic resonance imaging) are
likely to reveal mechanisms of sexual excitement, arousal,
orgasm and inhibition, and help to determine which mecha-
nisms can be altered by situational and pharmacological
interventions. In turn, the wealth of knowledge concerning
brain activation in laboratory species following sexual stimu-
lation can help to identify brain mechanisms for sexual
behavior that have converged and diverged during mam-
malian evolution. As more is known about the neurobiology
of sexual function and dysfunction, the more likely it will be
that sexual and reproductive problems can be targeted, mod-
elled and eliminated.
Acknowledgements
The work from the author’s laboratory reported in this review was
supported by grants from the Medical Research Council of Canada (MT-
13125), Natural Sciences and Engineering Research Council of Canada
(OGP-0138878), and Fonds pour la Formation de Chercheurs et l’Aide à la
Recherche du Québec (CE-98). The author would like to acknowledge the
scientific contributions of James Cantor, Tod Kippin, Wendy Smith, and
Carol Coopersmith.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• of special interest
•• of outstanding interest
1. Kippin TK, Talianakis S, Schattmann L, Bartholomew S, Pfaus JG:
•• Olfactory conditioning of sexual behavior in the male rat. J Comp
Psychol 1998, 112:389-399.
This study is the first report of conditioned ejaculatory preference in the male
rat. Such preferences are conditioned by pairing neutral odors (e.g. almond,
lemon) with copulation, and require ejaculation and a post-ejaculatory inter-
val in the presence of the CS+ odor as the unconditioned stimulus. It uses
a triad mating paradigm, in which a male is presented with two sexually
receptive females, one with the conditioned odor and one without, to assess
copulatory and ejaculatory preferences. The odors can also be paired with
access to nonreceptive females to produce inhibitory learning. This para-
digm is an important addition to the arsenal of behavioral tests, and will help
to reveal the neuroanatomy and pharmacology of excitatory and inhibitory
sexual conditioning.
2. Matuszczyk JV, Larsson K, Eridsson E: Subchronic administration of
fluoxetine impairs estrous behavior in intact female rats.
Neuropsychopharmacology 1998, 19:492-498.
3. Cantor J, Binik I, Pfaus JG: Chroinc fluoxetine inhibits sexual
• behavior in the male rat: reversal with oxytocin. Psychopharmacology
1999, 144:355-362.
This study demonstrates that daily fluoxetine treatment of male rats produces
a short-term inhibition of appetitive sexual behavior, but a longer-term
inhibition of ejaculation over a time course similar to that reported in male
humans. The inhibition of ejaculation was reversed by a small dose of oxy-
tocin, indicating that decreased oxytocin release before ejaculation may
cause the ejaculatory inhibition.
4. Srilatha B, Adaikan PG, Arulkumaran S, Ng SC: Sexual dysfunction
related to antihypertensive agents: results from the animal model.
Int J Impot Res 1999, 11:107-113.
5. Chan P, Liu JC, Tong YC, Chen YJ, Wang CC, Tomlinson B, Cheng JT:
Effects of losartan on the sexual behavior of male rats.
Pharmacology 1999, 58:132-139.
6. Manzo J, Cruz MR, Hernandez ME, Pacheco P, Sachs BD:
• Regulation of noncontact erection in rats by gonadal steroids.
Horm Behav 1999, 35:264-270.
This well-controlled study is notable for showing that androgens but not
estrogens stimulate noncontact erections, a homologue of psychogenic sex-
ual arousal in male rats. Because estrogens are capable of stimulating
mounting, the results of this study suggest that mounting and erection may
be stimulated by two distinct, but interactive, pathways in the brain.
7. Melis MR, Spano MS, Succu S, Argiolas A: The oxytocin antagonist
• D(CH2)5Tyr(Me)2-orn8-vasotocin reduces non-contact penile
erections in male rats. Neurosci Lett 1999, 265:171-174.
This study suggests that oxytocin and nitric oxide are involved in the stimu-
lation of noncontact erection. This information is important for our under-
standing of mechanisms involved in the facilitation and inhibition of
noncontact erections, and also for the potential pharmacological stimulation
of erection in individuals suffering from sexual arousal disorders.
8. Melis MR, Succu S, Spano MS, Argiolas A: Morphine injected into
the paraventricular nucleus of the hypothalamus prevents
noncontact penile erections and impairs copulation: involvement
of nitric oxide. Eur J Neurosci 1999, 11:1857-1864.
9. Moses J, Hull EM: A nitric oxide synthesis inhibitor administered
• into the medial preoptic area increases seminal emissions in an
ex-copula reflex test. Pharmacol Biochem Behav 1999, 63:345-348.
This study identifies the mPOA as one area in which nitric oxide stimulates
ejaculation.
10. Du J, Hull EM: Effects of testosterone on neuronal nitric oxide
•• synthase and tyrosine hydroxylase. Brain Res 1999, 836:90-98.
Dopamine release decreases in the mPOA following castration but is
restored with testosterone treatment. This study shows that nitric oxide syn-
thase, but not tyrosine hydroxylase, in the mPOA is stimulated by testos-
terone, which may also be the mechanism by which testosterone stimulates
dopamine release in the mPOA.
11. Liu YC, Sachs BD: Erectile function in male rats after lesions of
• the lateral paragigantocellular nucleus. Neurosci Lett 1999,
262:203-206.
Male rats with lesions of the lateral paragigantocellular nucleus had more
reflexive erections than males with sham lesions, but did not show any
change in the copulatory intromission ratio, or in the number of noncontact
erections. This suggests that reflexive and noncontact erections are stimu-
lated by two distinct, but perhaps interactive, neural pathways.
nb9610.qxd 12/03/1999 10:07 AM Page 757
12. Fiorino DF, Phillips AG: Facilitation of sexual behavior in male rats
•• following D-amphetamine-induced behavioral sensitization.
Psychopharmacology 1999, 142:200-208.
See annotation [13••].
13. Fiorino DF, Phillips AG: Facilitation of sexual behavior and
•• enhanced dopamine efflux in the nucleus accumbens of male
rats after D-amphetamine-induced behavioral sensitization.
J Neurosci 1999, 19:456-463.
These two studies [12••,13••] are part of an interesting series showing that
a single administration of amphetamine, which sensitizes mesolimbic
dopamine transmission in male rats, also sensitizes those males to acquire
appetitive and consummatory sexual behavior faster than nonsensitized
males. The sensitization process also increased the amount of dopamine
that was released in the nucleus accumbens during copulation.
14. Arletti R, Benelli A, Cavazzuti E, Scarpetta G, Bertolini A: Stimulating
property of Turnera diffusa and Pfaffia paniculata extracts on the
sexual behavior of male rats. Psychopharmacology 1999, 143:15-19.
15. Ang HH, Sim MK: Eurycoma longifolia increases sexual motivation
in sexually naive male rats. Arch Pharm Res 1998, 21:779-781.
16. Marin-Bivens CL, Kalra SP, Olster DH: Intraventricular injection of
neuropeptide Y antisera curbs weight gain and feeding, and
increases the display of sexual behaviors in obese Zucker female
rats. Regul Pept 1998, 75-76:327-334.
17. Rodriguez-Manzo G: Blockade of the establishment of the sexual
• inhibition resulting from sexual exhaustion by the Coolidge effect.
Behav Brain Res 1999, 100:245-254.
This study shows that the inhibition of male sexual behavior induced by cop-
ulation to sexual exhaustion can be delayed by presenting males with
different females. Thus, the Coolidge effect may work by delaying the induc-
tion of sexual inhibition.
18. Rodriguez-Manzo G: Yohimbine interacts with the dopaminergic
system to reverse sexual satiation: further evidence for a role of
sexual motivation in sexual exhaustion. Eur J Pharmacol 1999,
372:1-8.
19. Riters LV, Absil P, Balthazart J: Effects of naloxone on the
acquisition and expression of appetitive and consummatory
sexual behavior in male Japanese quail. Physiol Behav 1999,
66:763-773.
20. Riters LV, Absil P, Balthazart J: Effects of brain testosterone
•• implants on appetitive and consummatory components of male
sexual behavior in Japanese quail. Brain Res Bull 1998, 47:69-79.
This study shows that testosterone implants to the mPOA, but not the BNST,
can stimulate appetitive and consummatory sexual behavior in male
Japanese quail. This is important because it isolates the mPOA of this
species as playing a role in both appetitive and consummatory behaviors.
21. Balthazart J, Absil P, Gerard M, Appeltants D, Ball GF: Appetitive and
•• consummatory male sexual behavior in Japanese quail are
differentially regulated by subregions of the preoptic medial
nucleus. J Neurosci 1998, 18:6512-6527.
This study showed that lesions of discrete subregions of the mPOA in male
Japanese quail differentially disrupt appetitive or consummatory sexual
behaviors. This is important because it shows how the mPOA is organized
for the entire pattern of sexual behavior.
22. Cross E, Roselli CE: 17beta-estradiol rapidly facilitates
• chemoinvestigation and mounting in castrated male rats. Am J
Physiol 1999, 276:R1346-R1350.
This study shows that estradiol can stimulate ano-genital investigation and
mounting behavior quickly in short-term castrated male rats, an effect that is
too quick to involve a mechanism of gene transcription.
23. Coolen LM, Wood RI: Testosterone stimulation of the medial
• preoptic area and medial amygdala in the control of male hamster
sexual behavior: redundancy without amplification. Behav Brain
Res 1999, 98:143-153.
This study found no difference between the ability of testosterone implants
to the mPOA or medial amygdala, or both regions simultaneously, to stimu-
late copulation in castrated male hamsters. This suggests that true redun-
dancy exists in the brain, and that amplification from one site to another is
not required and does not occur for the stimulation of male copulatory
behavior by androgens.
24. Wood RI: Integration of chemosensory and hormonal input in the
male Syrian hamster brain. Ann NY Acad Sci 1998, 855:362-372.
25. Matuszewich L, Lorrain DS, Trujillo R, Dominguez J, Putnam SK,
Hull EM: Partial antagonism of 8-OH-DPAT’s effects on male rat
sexual behavior with a D2, but not a 5-HT1A, antagonist. Brain
Res 1999, 820:55-62.
Neurobiology of sexual behavior Pfaus 757
26. Rehman J, Kaynan A, Christ G, Valcic M, Maayani S, Melman A:
Modification of sexual behavior of Long–Evans male rats by drugs
acting on the 5-HT1A receptor. Brain Res 1999, 821:414-425.
27. Maswood N, Caldarola-Pastuszka M, Uphouse L: Functional
integration among 5-hydroxytryptamine receptor families in the
control of female sexual behavior. Brain Res 1998, 802:98-103.
28. Neckameyer WS: Dopamine modulates female sexual receptivity
• in Drosophila melanogaster. J Neurogenet 1998, 12:101-114.
Female Drosophila melanogaster flies were deprived of dopamine by the
addition of a tyrosine hydroxylase inhibitor to their diet. These females
showed decreases in sexual receptivity toward males, although the males
maintained their sexual interest, indicating that attractivity was not altered by
the treatment. Replacement with L-DOPA, the precursor eliminated by the
inhibition of tyrosine hyrdoxylase, restored sexual receptivity in the females.
29. Frye CA, Bayon LE, Pursnani NK, Purdy RH: The neurosteroids,
• progesterone and 3alpha,5alpha-THP, enhance sexual motivation,
receptivity, and proceptivity in female rats. Brain Res 1998,
808:72-83.
This paper reports on the ability of the progesterone metabolite 3α,5α-THP
to enhance appetitive and consummatory aspects of sexual behavior in
female rats. Previous studies by Frye and colleagues had established that
progesterone and this neurosteroid metabolite could facilitate sexual recep-
tivity rapidly in certain brain regions by interaction with GABA/benzodi-
azepine receptors. Finasteride, an inhibitor of progesterone’s metabolism
into 3α,5α-THP inhibited the preference of hormonally primed females for
sexually vigorous males, and reduced rates of proceptivity and receptivity.
This suggests that the ability of progesterone to facilitate appetitive and
consummatory sexual behaviors in the female rat may depend on its metab-
olism in the brain to a progestin that can act on both progesterone and
GABA receptors.
30. Pfaus JG, Smith WJ, Coopersmith CB: Appetitive and consummatory
sexual behaviors of female rats in bilevel chambers. I: A
correlational and factor analysis, and the effects of ovarian
hormones. Horm Behav 1999, 35:224-240.
31. Brandling-Bennett EM, Blasberg ME, Clark AS: Paced mating
behavior in female rats in response to different hormone priming
regimens. Horm Behav 1999, 35:144-154.
32. Ramos SM, DeBold JF: Protein synthesis in the medial preoptic
•• area is important for the mating-induced decrease in estrus
duration in hamsters. Horm Behav 1999, 35:177-185.
This fascinating study demonstrates that protein synthesis in the mPOA is
required for the well-established ability of vagino–cervical stimulation to
induce estrus termination. It is the first study to reveal a region of the brain
involved in estrus termination, and its implication of the mPOA has important
repercussions for our understanding of the way that genito-sensory stimuli
activate ‘future events’, that is, pathways that will be involved at a later time
in the termination of behavior.
33. Romeo RD, Parfitt DB, Richardson HN, Sisk CL: Pheromones elicit
• equivalent levels of Fos-immunoreactivity in prepubertal and
adult male Syrian hamsters. Horm Behav 1998, 34:48-55.
This is another study with important implications. Here, Fos immunocyto-
chemistry was used to mark cells that were activated in juvenile and adult
male hamsters following exposure to female hamster vaginal secretions. It
was found that pheromonal stimulation induced relatively equal amounts of
Fos in the brains of these animals, indicating that the sensory pathways that
convey pheromonal information relevant for the stimulation of sexual activity
are wired prior to puberty, despite the inability of prepubertal males to initi-
ate copulation. This suggests that androgens do not amplify the sensory
impact, but rather connect it to motor programs appropriate for copulation.
34. Kelkliher KR, Liu YC, Baum MJ, Sachs BD: Neuronal Fos activation
• in olfactory bulb and forebrain of male rats having erections in the
presence of inaccessible estrous females. Neuroscience 1999,
92:1025-1033.
This study used Fos to reveal brain regions of male rats that are activated
during noncontact erections evoked by bedding that contained female rat
estrous odors. Fos was enhanced in males showing noncontact erections in
subregions of the nucleus accumbens, anterior and posterior medial amyg-
dala, BNST, and mPOA, but not in olfactory bulb, compared with males that
did not show noncontact erections, or males given access to clean bedding.
35. Parfitt DB, Newman SW: Fos-immunoreactivity within the
•• extended amygdala is correlated with the onset of sexual satiety.
Horm Behav 1998, 34:17-29.
This study used Fos to reveal brain areas activated following sexual satiety
versus copulation. Fos clusters were found in nuclei within the medial amyg-
dala and BNST in males that ejaculated to satiety on four consecutive tests,
versus males that did not copulate. These sites may constitute part of a path-
way for sexual inhibition induced by satiety.
nb9610.qxd 12/03/1999 10:07 AM Page 758
758 Neurobiology of behaviour
36. Lumley LA, Hull EM: Effects of a D1 antagonist and of sexual
•• experience on copulation-induced Fos-like immunoreactivity in
the medial preoptic nucleus. Brain Res 1999, 829:55-68.
This study showed that Fos activation in the mPOA increases with sexual
experience, and that stimulation of D1 dopamine receptors may be respon-
sible for the augmentation of Fos induction in sexually experienced versus
naive males. This ties in nicely with the studies by Fiorino et al. [12••,13••]
showing that the sensitization of mesolimbic dopamine release by ampheta-
mine causes male rats to acquire sexual behavior faster. Sensitization of sev-
eral different dopamine systems by copulation may thus constitute a
common mechanism for the acquisition of unconditioned and conditioned
sexual responses.
37. Coolen LM, Peters HJ, Veening JG: Anatomical interrelationships of
• the medial preoptic area and other brain regions activated
following male sexual behavior: a combined Fos and tract-tracing
study. J Comp Neurol 1998, 397:421-435.
Fos induction in the mPOA following copulation in male rats was co-labelled
with anterograde and retrograde tracers in an effort to determine the function-
al pathways that relay information to and from the mPOA. Bidirectional con-
nections to the mPOA came from subregions of the BNST, postero-dorsal
preoptic nucleus, medial amygdala, and subparafascicular thalamic nucleus.
38. Foidart A, Meddle SL, Balthazart J: Mating-induced Fos and
aromatase are not co-localized in the preoptic area. Neuroreport
1999, 10:907-912.
39. Greco B, Edwards DA, Michael RP, Zumpe D, Clancy AN:
• Colocalization of androgen receptors and mating-induced Fos
immunoreactivity in neurons that project to the central tegmental
field in male rats. J Comp Neurol 1999, 408:220-236.
Copulation-induced Fos was found co-localized with androgen receptor in the
central tegmental field of the midbrain of male rats. Additional retrograde trac-
ing revealed connections to the mPOA, BNST, VMH and medial amygdala. It
is possible that androgens act in the central tegmentum to facilitate the trans-
mission of genito-sensory information to forebrain hypothalamic structures.
40. Frye CA, Vongher JM: Progesterone has rapid and membrane
• effects in the facilitation of female mouse sexual behavior. Brain
Res 1999, 815:259-269.
See annotation [43•].
41. Ogawa S, Eng V, Taylor J, Lubahn DB, Korach KS, Pfaff DW: Roles of
• estrogen receptor-alpha gene expression in reproduction-related
behaviors in female mice. Endocrinology 1999, 139:5070-5081.
See annotation [43•].
42. Ogawa S, Washburn TF, Taylor J, Lubahn DB, Korach KS, Pfaff DW:
• Modification of testosterone-dependent behaviors by estrogen
receptor-alpha gene disruption in male mice. Endocrinology 1999,
139:5058-5069.
See annotation [43•].
43. Honda S, Harada N, Ito S, Takagi Y, Maeda S: Disruption of sexual
• behavior in male aromatase-deficient mice lacking exons 1 and 2
of the cyp19 gene. Biochem Biophys Res Commun 1998,
252:445-449.
These four studies show the power of transgenic mouse preparations when
they are used properly to analyse mechanisms of behavior. Progesterone
was found to facilitate lordosis in females with a deletion of the progesterone
receptor (PRKO), suggesting that progesterone may act on substrates other
than the intracellular progestin receptor to facilitate lordosis. Female mice
with a deletion of the α form of the estrogen receptor (ERKO) did not dis-
play lordosis following hormone treatment, but instead were highly aggres-
sive toward males that attempted to mount them. These females also lacked
parental behavior and were more likely to engage in infanticide. In contrast,
ERKO males lacked offensive aggression compared with wild-type males,
but both testosterone and dihydrotestosterone were capable of restoring
mounting behavior. Although these results suggest that the α form of the
estrogen receptor is not necessary for the stimulation of male sexual behav-
ior by androgens in mice, male mice with a deletion of the aromatase gene
(ArKO) had longer latencies to initiate sexual activity.
44. Halpern CT, Udry JR, Suchindran C: Monthly measures of salivary
• testosterone predict sexual activity in adolescent males. Arch Sex
Behav 1998, 27:445-465.
This study showed that testosterone measures from the saliva of heterosex-
ual adolescent men correlated positively with the number of times they initi-
ated sexual contact. Measures of circulating androgens may thus predict
sexual contact, although it remains to be determined whether sexual contact
led to the increases in androgens.
45. Flynn MA, Weaver-Osterholtz D, Sharpe-Timms KL, Allen S, Krause G:
Dehydroepiandrosterone replacement in aging humans. J Clin
Endocrinol Metab 1999, 84:1527-1533.
46. Sarrel P, Dobay B, Wiita B: Estrogen and estrogen-androgen
• replacement in postmenopausal women dissatisfied with
estrogen-only therapy. Sexual behavior and neuroendocrine
responses. J Reprod Med 1998, 43:847-856.
This well-controlled study showed that the combination of estrogen and
androgen was more effective than estrogen alone in stimulating sexual
desire, arousal and copulation in postmenopausal women. Androgens thus
play a key role in sexual desire and satisfaction in human females.
47. Kruger T, Exton MS, Pawlak C, von zur Muhlen A, Hartmann U,
•• Schedlowski M: Neuroendocrine and cardiovascular response to
sexual arousal and orgasm in men. Psychoneuroendocrinology
1998, 23:401-411.
See annotation [48••].
48. Exton MS, Bindert A, Kruger T, Scheller F, Hartmann U, Schedlowski M:
•• Cardiovascular and endocrine alterations after masturbation-
induced orgasm in women. Psychosom Med 1999, 61:280-289.
These two studies [47••,48••] examined cardiovascular and endocrine cor-
relates of sexual orgasm in men and women. Orgasm induced a long-term
increase in plasma prolactin levels of both men and women, whereas arousal
increased cardiovascular responses in both men and women, but produced
small increases in plasma concentrations of luteinizing hormone and testos-
terone only in women.
49. Blaicher W, Gruber D, Bieglmayer C, Blaicher AM, Knogler W, Huber
JC: The role of oxytocin in relation to female sexual arousal.
Gynecol Obst Invest 1999, 47:125-126.
50. Stoleru S, Gregoire MC, Gerard D, Decety J, Lafarge E, Cinotti L,
•• Lavenne F, Le Bars D, Vernet-Maury E, Rada H et al.:
Neuroanatomical correlates of visually evoked sexual arousal in
human males. Arch Sex Behav 1999, 28:1-21.
This is the first published study of neuroanatomical activation in human brains
following visually evoked sexual arousal. Positron emission tomography (PET)
was used to identify activation in human males following exposure to sexually
explicit, humorous or emotionally neutral film clips. Sexual arousal was asso-
ciated with bilateral activation of the inferior temporal cortex, right insular and
inferior frontal cortex, and left anterior cingulate cortex. The latter two regions
are considered paralimbic and play a role in the processing of sensory infor-
mation related to motivation and autonomic functions. The degree of activa-
tion in these regions also correlated positively with plasma testosterone
concentrations. It is expected that more studies of human brain activation by
sexual stimuli will follow that utilize both PET and MRI technologies.