Scandinavian Journal of Psychology, 2003, 44, 257-263
Pharmacological and physiological aspects of sexual exhaustion
in male rats
ALONSO FERNANDEZ-GUASTI and GABRIELA RODRIGUEZ-MANZO
Departamento de Farmacobiologia, Cinvestav, Mexico
Fernandez-Guasti, A. & Rodriguez-Manzo, G. (2003). Pharmacological and physiological aspects of sexual exhaustion in male rats.
Scandinavian Journal of Psychology, 44, 257-263.
The present article reviews the current findings on the interesting phenomenon of sexual satiety. Knut Larsson in 1956 reported on the develop-
ment of sexual exhaustion in the male rat after repeated copulation. We have studied the process and found the following results. (I) One day
after 4 hours of ad libitum copulation, two-thirds of the population showed complete inhibition of sexual behavior, while the other third displayed
a single ejaculatory series from which they did not recover. (2) Several pharmacological treatments, including 8-OH-DPAT, yohimbine, naloxone
and naltrexone, reverse this sexual satiety, indicating that the noradrenergic, serotonergic and opiate systems are involved in this process. Indeed,
direct neurochemical determinations showed changes in various neurotransmitters during sexual exhaustion. (3) Given enough stimulation,
by changing the stimulus female, sexual satiety was prevented, suggesting that there are motivational components of the sexual inhibition that
characterizes sexual exhaustion. (4) The GABA antagonist bicuculline, or the electrical stimulation of the medial preoptic area, did not reverse
sexual exhaustion. These data suggest, on the one hand, that sexual exhaustion and the postejaculatory interval (which is shortened by
bicuculline administration) are not mediated by similar mechanisms and, on the other, that the medial preoptic area does not regulate sexual
satiety. (5) The androgen receptor density in brain areas closely related to the expression of masculine sexual behavior, such as the medial
preoptic nucleus, was drastically reduced in sexually exhausted animals. Such reduction was specific to certain brain areas and was not related
to changes in the levels of androgens. These results suggest that changes in brain androgen receptors account for the inhibition of sexual behavior
present during sexual exhaustion. (6) The recovery process of sexual satiety after 4 hours of ad libitum copulation reveals that, after 4 days,
only 63% of the males are able to show sexual behavior while after 7 days all animals display copulatory activity.
Key words: Sexual satiety, sexual exhaustion, motivation, postejaculatory interval, brain androgen receptors.
Dr Alonso Ferndndez-Guasti, Departamento de Farmacobiologia, Cinvestav, Calz. De 10s Tenorios 235, Col. Granjas Coapa, Mexico 14330 D.F.,
Mexico. E-mail: firstname.lastname@example.org
Knut Larsson published in 1956 his excellent thesis on the
sexual behavior of the male albino rat, in which a thorough
revision of all aspects of this behavior was conducted
(Larsson, 1956). The careful and systematic study of the
laboratory rat's male sexual behavior in this thesis, including
the analysis of the laboratory conditions, the methods of
observation and the influence of factors such as age, endocrine
stage and diurnal variations, provided a valuable basis that
allowed progress in this field. Knut Larsson included a chapter
in that thesis describing the process of sexual satiation.
Sexual exhaustion or sexual satiation is a phenomenon
that appears after repeated ejaculation. The main feature of
this phenomenon is the natural instatement of a long-lasting
inhibition of sexual behavior. The exhaustion phenomenon
was described in male rats (Beach & Jordan, 1956; Larsson,
1956) and interest centred on the male's copulatory perform-
ance and capacity. Thus, the study of the development,
recovery and influence of external stimuli on the sexual
capacity and performance of males characterized the initial
approaches to the phenomenon. Although most of the data
regarding sexual exhaustion have been obtained in rats, the
phenomenon has also been described for other mammalian
species, including hamsters (Beach & Rabedeau, 1959;
Bunnell et al., 1976), rhesus macaques (Bielert & Goy, 1973;
Phoenix & Chambers, 1988) and bulls (Almqvist & Hale, 1956).
SEXUAL EXHAUSTION: DEVELOPMENT
Knut Larsson described in his thesis the features of sexual sati-
ation based on a series of experiments performed in 1954. In
the first experiment he analyzed the effects of mild sexual
activity on further sexual behavior. The experimental schedule
was as follows. Sexually experienced males were allowed one
hour of sexual activity every fourth day three times, followed
by additional sexual behavior for one hour every third day
four times. Male sexual behavior was recorded on the last
test of each schedule segment. Finally, they were allowed
to recover for one month and recorded for sexual behavior
The results of this experiment were summarized by Knut
Larsson as follows:
Sexual satiation occurred when the animals were not allowed
to recover from one hour of activity. It was characterized by
the following changes:
(1) A diminished number of ejaculations and intromissions
and an increase in the number of incomplete copulations.
(2) A slight increase in the length of the series of copulations
but no differences in the frequencies of intromissions. A
slight decrease in the intromission per minute, especially
at the end of the observation.
O 2003 The Scandinavian Psychological Associations. Published by Blackwell Publishing Ltd., 9600 Garsington Road, Oxford OX4 2DQ, UK
and 350 Main Street, Malden, MA 02148, USA. ISSN 0036-5564.
258 A. Fernandez-Guasti and G. Rodriguez- Munzo
Scand J Psycho1 44 (2003)
(3) A steady and very regular prolongation of the refractory
period takes place.
In a second experiment he analyzed the effects of pro-
nounced sexual satiation. In this case animals were allowed
to copulate ad libitum during one hour for five consecutive
days. On the fifth day the activity was recorded. In his thesis
Knut Larsson wrote:
Summarising the results of this as well as the previous
investigation, we find. . . :
(1) No or only slight change in the number of intromissions
preceding each ejaculation.
(2) A slight prolongation of the duration of each series of
copulations, especially in the last series.
(3) A lowered number of intromissions per minute, especially
at the end of the observation.
(4) Highly prolonged refractory periods.
Knut Larsson concluded that sexual satiation appears after
a particular sexual behavior pattern elicited by repeated
ejaculation. He carefully analyzed that pattern and found a
progressive diminishing of the number of intromissions, an
increase in the number of attempts (mounts), prolonged
refractory periods and finally a lowering of the intensity of
the reflex (intromissions per minute) as exhaustion appro-
ached. According to Knut Larsson, sexual satiation is
primarily to be traced in the length of the refractory periods.
Since 1956 few research groups have studied sexual
exhaustion. Different schedules have been used to develop
sexual satiety and different criteria used for sexual exhaus-
tion. However, in spite of these variations, the changes in
sexual activity as sexual satiation develops, as described by
Knut Larsson in his thesis, have been confirmed.
Most research groups have focused on the development
rather than on the consequences of sexual satiation. Hence,
Beach and Jordan (1956) considered sexual satiation as a
catabolic process whose endpoint is fatigue and whose
sequel is a period of recovery. Lawrence and Barfield (1975)
suggested that sexual exhaustion is the result of a build-up
of the refractory period that rises asymptotically as exhaus-
tion approaches. Satiation occurs when the animal fails to
re-arouse after cessation of the last active behavioral inhibi-
tion, that is, the last absolute refractory period.
In 1994 we reported on the development of sexual satiety
after a particular paradigm (Rodriguez-Manzo & Fernindez-
Guasti, 1994). Sexually experienced male rats were allowed
to mate ad libitum with a single receptive female and sexual
behavior was recorded until a postejaculatory interval of
90 min occurred. If the rat did not copulate within this
period, it was considered sexually exhausted. All animals
accomplished this sexual satiation criterion within 4 hours
of ad libitum copulation. A median number of 7 ejaculatory
series was achieved before reaching the sexual exhaustion
criterion; however, this number varied from 5 to 12. Analysis
of sexual exhaustion development revealed that as the rat
approached sexual satiation, the number of mounts did not
change, while the number of intromissions decreased, the
ejaculation latency tended to increase (though this did
not reach statistical significance) and the postejaculatory
interval increased logarithmically. In contrast to the earlier
studies on sexual exhaustion, we became interested in the
inhibitory period itself, once established. Thus, we found
that 24 hours after the sexual satiation session, two-thirds of
the exhausted animals did not show sexual behavior in the
presence of a receptive female and one-third were able to
execute one ejaculatory series, from which they did not
recover. These proportions prevailed after increasing the
observed population (to more than 100 animals). implying
that sexual exhaustion can be expressed in two different
ways: by the complete absence of sexual activity or by the
execution of one ejaculatory series without recovery. When
present, this ejaculatory series shows particular features: the
intromission latency and number of mounts are increased
and the number of intromissions decreased, compared with
a first ejaculatory series of a rested male. But the most con-
spicuous feature of the sexual behavior shown by sexually
exhausted rats is their inability to resume copulation after
ejaculation. The involvement of physical exertion in the
behavioral inhibition exhibited by the exhausted animals
24 hours after the satiation procedure was discarded, since
we evaluated the spontaneous ambulatory behavior of these
and control males and found no differences (Rodriguez-
Manzo & Fernandez-Guasti, 1994).
Once a male reaches the state of sexual exhaustion it
recovers slowly. The process of recovery of sexual behavior
has been little investigated. Knut Larsson in his thesis
reported that, 14 days after sexual activity, the satiated
animals behaved similarly to control rats (Larsson, 1956).
Beach and Jordan found that a 6-day resting period was not
enough for sexual recovery after satiation, but a 15-day
period of sexual inactivity rendered fully rested males cap-
able of maximal copulatory performance (Beach & Jordan,
1956). Lawrence and Barfield conducted an interesting ana-
lysis of two components of the refractory period during
both the development of and recovery from sexual exhaus-
tion. They demonstrated that, by day 6 after satiation,
pre-ejaculatory measures of sexual behavior as well as the
absolute refractory period had returned to baseline values
while the relative refractory period was still extended
(Lawrence & Barfield, 1975).
Recently, we began to explore the recovery process of sex-
ual activity after a 4-hour ad libitum copulatory session with
a single female, by studying sexual behavior after various
intervals in the same subjects. In the testing scheme, males
were exposed to receptive females on two consecutive days
after satiation (24 h and 48 h recordings) and thereafter a
one-day pause was allowed (next recording at 96 h). Prelim-
inary data show that, 48 h after the development of sexual
2003 The Scandinavian Psychological Associations.
Scand J Psycho1 44 (2003)
Sexual exhaustion in male rats 259
Table I. Recowry profile of sexual activity after copula/iott to
satiation in male rats
Day 1 Day 2
The values represent the percentages of sexually exhausted male rats
that were able to show mounts (M), intromissions (I), ejaculation
(E) and to resume copulation after ejaculation (CR) at the different
time intervals after the sexual exhaustion session (copulation to
satiation on day 0).
satiation, no animal copulated, but after 96 h 63% of the
exhausted males ejaculated and resumed copulation. Seven
days after satiation 100% of the subjects ejaculated and
resumed copulation. The complete inhibition of sexual
activity seen at the 48 h observation is, of course, influenced
by both the repeated copulation during the development
of sexual satiety and by the sexual activity shown by these
males in the 24 h test. To discern the effects of these two
factors, an independent group of animals was tested for
sexual behavior 48 h but not 24 h after sexual satiety. In
the latter group, 12.5% of the animals initiated sexual activ-
ity, which consisted mainly of mounts and a few intromis-
sions without attaining ejaculation, in a 30-min period.
The 96 h data reveal that, already at 4 days after copulation
to exhaustion, an important percentage of the males (63%)
not only exhibited ejaculation, but also recovered the
capacity to resume copulation. seven days after copulation
all animals were capable of executing one copulatory series.
These data are shown in Table 1. Note that the return to
basal values in the sexual behavior parameters seen 7 days
after satiety does not imply the recovery of the ejaculatory
capacity of a fully rested male, since only one copulatory
series was recorded.
In relation to the ejaculatory capacity of sexually experi-
enced male rats, several authors made an interesting observa-
tion in the early 1960s: When a male rat ceased to copulate,
due to the attainment of sexual exhaustion, a change in the
female partner renewed its sexual responsiveness, including
the accomplishment of ejaculation (Fisher, 1962; Fowler &
Whalen, 1961; Hsiao, 1969; Wilson et al., 1963; Zucker &
Wade, 1968). This phenomenon was named "the Coolidge
effect" (Wilson et a!., 1963) and it was presumed to be due
to an increase in sexual motivation or renewal of sexual
interest based on the incentive stimulus that a new female
represented to the exhausted male. Based on these data, we
decided to examine the effect of a "physiological increase"
O 2003 The Scandinavian Psychological Associations.
in sexual motivation provided by the Coolidge effect on the
sexual performance of sexually exhausted males 24 hours
after the exhaustion procedure. The results revealed that
the copulatory capacity of male rats is far greater than is
spontaneously exhibited during a satiation session with a
single female. In response to the change in the stimulus
female, male rats were able to maintain copulatory activity
for at least four more hours (eight hours of continuous
copulation as a whole). In fact, the recording session was
ended because of the termination of the dark phase of the
lightdark cycle and the decrease in the females' receptivity
that resulted from prolonged sexual activity. Interestingly,
when these males were exposed to a receptive female the
day after, 80% showed ejaculation and 50% resumed copula-
tion after ejaculation. These data led to the conclusion
that sexual motivation can preclude the establishment of
the process responsible for the sexual inhibition that follows
sexual satiation (Rodriguez-Manzo, 1999b).
PHARMACOLOGICAL ANALYSIS OF SEXUAL
The neurochemical examination of the satiation phenom-
enon was almost absent until 1987, when James Pfaus and
Boris Gorzalka explored the effect of opioid antagonists on
the development of sexual satiation. These authors found
that naloxone retarded sexual exhaustion, since the mean
time the rats spent copulating was increased but without
modification of the ejaculatory capacity (Pfaus & Gorzalka,
1987). Some research groups, including our own, have
studied several neurotransmitter systems: opioids (Miller &
Baum, 1987; Pfaus & Gorzalka, 1987; Rodriguez-Manzo &
Fernandez-Guasti, 1995a; Rodriguez-Manzo et al., 2002a),
noradrenaline (Fernandez-Guasti & Rodriguez-Manzo,
1997; Rodriguez-Manzo & Fernandez-Guasti, 1994, 1995b),
serotonin (Fernindez-Guasti & Rodriguez-Manzo. 1997;
Rodriguez-Manzo & Fernandez-Guasti, 1994; Yells el a!.,
1992), dopamine (Mas rt al., 1995a,b; Rodriguez-Manzo,
1999a) and GABA (Rodriguez-Manzo et. al., 2000). Most
neurotransmitter systems seem to participate in the regula-
tion of this interesting phenomenon via a common norad-
renergic link (Rodriguez-Manzo & Fernandez-Guasti, 1995b),
which in turn is coupled to a dopaminergic final pathway
Below we review both the role of the potent 5-HT,, agon-
ist 8-OH-DPAT, and the interesting putative participation
of GABA-ergic neurotransmission in sexual exhaustion.
These aspects were selected because of the great importance
of the contributions of Knut Larsson to both.
To recap, 24 hours after intense copulation in a sexual
exhaustion session, one-third of the population showed a
single ejaculation, after which they did not resume copula-
tion, and two-thirds did not show sexual behavior at all. All
the data here reported concerning our pharmacological and
endocrine studies were obtained at this time.
260 A. Fernandez-Guasti and G Rodriguez-Manzo
Scand J Psycho1 44 (2003)
Serotonin (5-hydroxytryptamine, 5-HT) has an inhibitory
effect on most aspects of male sexual activity. Experimental
manipulations which reduce endogenous 5-HT activity in-
clude lesions of 5-HT neurons with 5,7-dihydroxytryptamine
(5,7-DHT) (Fernandez-Guasti & Escalante, 1991; Larsson
et al., 1978) or inhibition of 5-HT synthesis using p-
chlorophenylalanine (pCPA) (Ahlenius et al., 1971;
Fernandez-Guasti & Escalante, 199 1; Salis & Dewsbury,
1971), and these manipulations stimulate sexual activity.
Furthermore, the effects of pCPA can be reversed by systemic
treatment with the precursor of 5-HT, 5-hydroxytryptophan
(5-HTP). Finally, the central administration of 5-HT inhibits
sexual activity when injected into the medial preoptic area
(mPOA) and the nucleus accumbens (Fernandez-Guasti
et a]., 1992; Verma et al., 1989).
The finding of several serotonin receptors has raised the
question of the functional link between these receptors and
the mediation of the inhibitory effects of serotonin on
copulatory behavior. We. together with Knut Larsson, Sven
Ahlenius and Anders Agmo, proposed that the SHT,,
receptor mediates these inhibitory actions. Evidence for
this proposal includes the fact that the systemic or intra-
brain administration of 5-HT,, agonists inhibits male sex-
ual behavior similarly to serotonin or its precursor 5-HTP
(Fernandez-Guasti et al., 1989, 1992; Hillegaart & Ahlenius,
1998). Also, the co-administration of 5-HTP and a 5-HT,,
agonist, at doses that are subthreshold to inhibit male rat
sexual activity, synergistically interact to inhibit this behavior
(Fernandez-Guasti & Rodriguez-Manzo, 1992). Addition-
ally, selective 5-HT,, receptor antagonists completely block
the inhibitory effect of 5-HTP on copulation, while antag-
onists to other 5-HT receptor subtypes do not (Ahlenius
& Larsson, 1998). The recent development of knockout
mice strains with a targeted deletion of genes encoding for
specific serotonin receptor proteins provides a new approach
to the analysis of their role in masculine sexual behavior.
Thus, in 5-HT,, receptor knockout mice we found that spon-
taneous sexual behavior appeared to be facilitated, in the
sense that the animals became interested earlier in sexual
activity, although they required more stimulation to achieve
ejaculation than the corresponding wild-type strain
(Rodriguez-Manzo et al., 2002b). It has to be mentioned
that in that work the inhibitory actions of serotonin on
mouse sexual behavior were found to be mediated by 5-HT,,
receptors, but also by the 5-HT,, subtype. This species dif-
ference between mice and rats makes it difficult to draw con-
clusions about a unique role of the 5-HT,, receptor subtype
in the control of masculine sexual behavior of rodents; how-
ever, the inhibitory effect of the 5-HT,, receptor subtype was
confirmed. Whether an increase in 5-HT,, receptor number
or affinity participates in the inhibition of male rat sexual
behavior observed after copulation to exhaustion remains to
be studied. Naturally, the introduction of new selective 5-
HT,, antagonists will shed light on the role of this receptor
in sexual exhaustion.
In 1981, Knut Larsson and coworkers demonstrated that
the administration of a then new, selective 5-HT agonist,
8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT), pro-
duced a drastic facilitation of copulatory behavior in male
rats. In an extensive and detailed analysis of this effect, it
was established that such facilitation was mediated by the
stimulation of central 5-HT,, receptors (Ahlenius et al.. 198 1).
The behavioral effects of 8-OH-DPAT on masculine sexual
activity (Ahlenius & Larsson, 1991) consisted primarily of a
large reduction in the number of intromissions preceding
ejaculation, a drastic shortening of the ejaculation latency
and an increase in the percentage of sluggish animals that
displayed sexual behavior.
The facilitatory actions of this drug were so clear that, in
1994, we decided to use 8-OH-DPAT as a pharmacological
tool to attempt the putative reversal of sexual satiety. The
initial approach of that study was to establish whether the
profound inhibition of sexual behavior produced by sexual
satiety could be reversed by pharmacological means. A dose
of 0.25 mg/kg of 8-OH-DPAT clearly reversed the sexual
inhibition characteristic of sexual exhaustion, in the sense
that 24 h after satiation the animals were able to resume
copulatory behavior after ejaculation and that the propor-
tion of sexually exhausted rats showing mounts, intromis-
sions and ejaculation was increased. Thus, 8-OH-DPAT
treatment induced 90% of the animals to display sexual
behavior until ejaculation, whereas around 30% of the studs
did so in the control group. Furthermore, almost no control
sexually exhausted males resumed copulation after ejaculat-
ing once (4%), while 71% of those treated with 8-OH-DPAT
were able to reinitiate sexual activity after ejaculation
(Rodriguez-Manzo & Fernandez-Guasti, 1994). Interestingly,
our data with 8-OH-DPAT revealed that the satiated animals
responded to drug administration with the typical features
described for this compound in non-exhausted animals,
that is, a significant dose-dependent reduction in the
number of mounts and intromissions preceding ejaculation
and a drastic shortening of ejaculation latency (Ahlenius &
In later studies we established that the integrity of the
central noradrenergic system was essential for the facilitat-
ory action of 8-OH-DPAT on the sexual activity of sexually
exhausted male rats, since after its lesion the SHT,, re-
ceptor agonist completely lost its effect (Rodriguez-Manzo
& Fernandez-Guasti, 1995b). Moreover, in non-exhausted
male rats, neurochemical lesion of the noradrenergic system
only partially blocked the facilitatory actions of 8-OH-
DPAT, suggesting that sexual exhaustion contributed to
completely abolish the facilitatory drug effect (Fernandez-
Guasti & Rodriguez-Manzo, 1997). At that time no obvious
explanation for the contribution of sexual exhaustion to the
cancellation of 8-OH-DPAT effects could be provided. How-
ever. recent findings on changes in androgen receptor density
Q 2003 The Scandinavian Psychological Associations.
Scand J Psychol 44 (2003)
Sexual exhaustion in mule ruts 261
in the brain provide a clue to the interpretation of these
results (see below).
In 1986, we published in collaboration with Knut Larsson a
series of articles on the role of the GABA-ergic system in the
control of masculine sexual behavior. The main finding of
those experiments was the very drastic shortening of the
postejaculatory interval (and of the ultrasonic vocalization
emission that characterizes this period) after the intrapre-
optic injection of GABA, antagonists or inhibitors of GABA
synthesis (Fernandez-Guasti et ul., 1986). These results led
to the proposition that GABA serves an inhibitory role in
the control of masculine sexual behavior, primarily during
the postejaculatory interval. Indeed, in 1986 it was estab-
lished that, after ejaculation, there is an increase of GABA
levels in the cerebrospinal fluid of male rats (Qureshi &
Sodersten, 1986). As mentioned above, the development of
sexual satiety is characterized by a progressive prolongation
of the postejaculatory interval. Actually, most animals stop
copulating after ejaculation. Thus, the inhibition of sexual
behavior that follows copulation to exhaustion could be
interpreted as a very prolonged postejaculatory interval.
The data of Lawrence and Barfield showing the progressive
increase in the relative refractory period as sexual exhaus-
tion develops, together with the fact that 6 days after satia-
tion the relative refractory period is the only sexual behavior
measure that is still extended, further supported this idea
(Lawrence & Barfield, 1975).
To analyze this hypothesis, we explored whether adminis-
tration of the GABA, antagonist bicuculline directly into
the mPOA reversed sexual exhaustion (Rodriguez-Manzo,
et al., 2000). Although this same treatment was shown to
stimulate sexual behavior by reducing the duration of the
postejaculatory interval in non-satiated rats (Fernindez-
Guasti et al., 1986) it lacked effect in sexually exhausted
animals. This finding revealed that a different mechanism
underlies the inhibition of sexual behavior that characterizes
the postejaculatory interval and the one exhibited after
sexual satiation. Interestingly, a similar result was obtained
after electrical stimulation of the mPOA (Rodriguez-Manzo
et al., 2000). Thus, as previously reported (for review see
Paredes in this volume) the stimulation of this brain area
produces a clear facilitation of sexual behavior in non-
exhausted, sexually experienced studs, but lacks an effect in
sexually satiated males (Rodriguez-Manzo et al., 2000).
It has been reported that the androgen-sensitive neurons in
the mPOA participate in the regulation of copulation, since
implantation of testosterone into this brain area of castrated
male rats restores sexual behavior, while selective blockade
of androgen receptors (AR) in this region inhibits mating
O 2003 The Scandinavian Psychological Associations.
EXH SEXP 1EJ EXH
Fig. 1. Comparison of the androgen receptor (AR) density in the
medial preoptic nucleus (MPN) and the bed nucleus of the stria
terminalis (BST) of control sexually experienced males (SEXP) and
rats that ejaculated once (1EJ) or copulated to exhaustion (EXH).
Data are expressed as proportional area (i.e. the sum of the stained
particle areaslevaluated area). Tukey test **p < 0.01; ***p < 0.001.
(McGinnis et al., 1996). More direct evidence comes from
recent molecular biology studies showing that mating-
induced Fos expression occurs almost exclusively in AR-
containing neurons located in the mPOA (Greco et al.,
In a recent study, we analyzed whether sexual activity
altered AR immunoreactivity (Fernandez-Guasti et al.,
2003) in areas closely related to the neural andlor neuro-
endocrine control of sexual behavior, such as the medial
preoptic nucleus (MPN) and the bed nucleus of the stria
terminalis (BST) (see Meisel & Sachs, 1994). We hypothes-
ized that changes in the androgen receptor density (ARD)
could mediate the long-term alterations in sexual behavior
produced by copulation. The results were compared between
sexually sated rats, animals that had one ejaculation and
sexually experienced subjects that had not recently copu-
lated. The data obtained revealed a reduction in ARD in
the MPN, but not in the BST. Interestingly, in the MPN
this reduction was proportional to the quantity of sexual
behavior displayed, since after sexual satiation fewer cells
appeared marked as compared with those stained in rats
that ejaculated once (see Fig. 1). These results suggest that
a drastic decrease in ARD in specific brain regions might
play a role in the inhibition of sexual behavior observed in
sexually sated males.
Interestingly, the changes in ARD during sexual satiety
could provide a key to understand a possible interaction
between the function of neurotransmitter systems linked
to endocrine processes. In particular, as aforementioned,
8-OH-DPAT had an action in noradrenergic-lesioned
262 A. Fernimdez-Guasti and G Ko(lri~uez-Manzo
Scand J Psycho1 44 (2003)
non-sexually exhausted rats, whereas in sexually satiated
animals with a noradrenergic lesion the drug completely
lacked of an effect. We here propose that such difference
in 8-OH-DPAT effect could be mediated, at least partially,
by changes in ARD. As early as 1985, Clark and colleagues
suggested that the effects of testosterone on male rat sexual
behavior could be partially mediated by the noradrenergic
system, since yohimbine injection stimulated mounting
and intromission in long-term castrated rats (Clark el al.,
1985). Later, Bancroft supported that proposal and extended
the notion, of noradrenaline mediating androgen effects,
to human sexual arousal (Bancroft, 1995). There have also
been several reports suggesting that 8-OH-DPAT interacts
with testosterone to stimulate male rat sexual behavior
(Haensel et al., 1993; Mendelson & McEwen, 1990; Rowland
& Houtsmuller, 1998). Finally, the interaction of 8-OH-
DPAT with alpha,-adrenoceptors is well documented. Taking
these data together, it emerges that 8-OH-DPAT interacts
with both testosterone and the noradrenergic system to exert
its facilitatory actions on male rat sexual behavior, which
would explain the partial and complete blockade of its
effects found in sexually experienced and sexually exhausted
lesioned rats, respectively. Thus, in the absence of the
noradrenergic system, 8-OH-DPAT showed an attenuated
facilitatory effect in sexually experienced males. However,
with a concomitant lack of testosterone action, due to the
sexual exhaustion-induced drastic reduction in ARD, the
effects of 8-OH-DPAT were completely blocked. Naturally
this proposition requires experimental support.
Knut Larsson first described the process of sexual exhaus-
tion, and indicated that this process develops rapidly, in
terms of hours, after repeated copulation and recovers gra-
dually during a long-term period, of several days. Interest-
ingly. if continued stimulation is provided to the male, the
sexual inhibition does not appear, suggesting that increased
sexual motivation may overcome such inhibition. Using the
paradigm of continuous copulation during a 4-hour period,
we have found that, 24 hours later, most males show a com-
plete inhibition of sexual behavior, while a third of the popu-
lation can copulate to ejaculation. after which they do not
resume copulation. The analysis of the recovery process
showed a progressive increase in the proportion of males
ejaculating and resuming copulation within one week after
sexual exhaustion. The inhibition of sexual behavior after
sexual exhaustion does not rely on motor tiredness.
In the pharmacological analysis of sexual satiety, others
and we have established that various treatments, including
serotonergic, dopaminergic, opioid and noradrenergic drugs,
could reverse sexual exhaustion. In the action of most of
these drugs, the noradrenergic and dopaminergic systems
seem essential. The SHT,, receptor subtype most likely
mediates the inhibitory action of serotonin on masculine
sexual behavior; however, its role on sexual satiety remains
to be studied. Interestingly, neither the administration of
GABA antagonists nor the electrical stimulation of the
mPOA reversed sexual exhaustion, leading to the conclusion
that this process does not represent a very prolonged post-
Finally, sexual behavior, and to a larger extent copulation to
satiation, reduced the ARD in brain areas closely related to the
expression of sexual behavior, suggesting an endocrine link in
the mediation of this process. This interesting finding also opens
the possibility of interactions between pharmacological and
endocrine processes in the regulation of sexual satiety.
Ahlenius, S., Eriksson, H., Larsson, K., Modigh, K. & Sodersten,
P. (1971). Mating behavior in the male rat treated with p-
chlorophenylalanine methyl ester alone and in combination
with pargiline. Psychophurmacology, 20, 383-388.
Ahlenius, S. & Larsson, K. (1991). Physiological and pharmacolo-
gical implications of specific effects by 5HT,, agonists on rat sex-
ual behaviour. In R. J. Rodgers & S. J. Cooper (Eds.), 5-HT,,
agonists, 5-HT, untugonists and betcodiuzepines: Their compara-
tive behaviourul pharmacology (pp. 28 1-3 15). Chichester: John
Wiley & Sons.
Ahlenius, S. & Larsson, K. (1998). Evidence for the involvement of
5-HT,, receptors in the inhibition of male rat sexual behaviour
produced by 5-HTP. Psychopharmacology (Berlin), 137, 374-
Ahlenius, S., Larsson, K., Svensson. L., Hjorth, S., Carlsson, A,,
Lindberg, P, Wikstrom, H., Sanchez, D., Arvidsson, L. E.,
Hacksell, U. & Nilsson, J. L. G. (1981). Effects of a new type of
5-HT receptor agonist on male rat sexual behaviour. Pharmaco-
logy, Biochemistry crnd Behavior, 15, 785-792.
Almqvist, J. 0. & Hale, E. B. (1956). An approach to the measure-
ment of sexual behavior and semen production in dairy bulls.
Proceedings of' the Congress on Animal Reproduction, 3, 50-59.
Bancroft, J. (1995). Are the effects of androgens on male sexuality
noradrenergically mediated? Some consideration of the human.
Neuroscience and Biobehavioral Reviews, 19, 325-330.
Beach, F. A. &Jordan, L. (1956). Sexual exhaustion and recovery in the
male rat. Quarterly Journal of Experimental Psychology, 8. 12 1-1 33.
Beach, F. A. & Rabedeau, R. G. (1959). Sexual exhaustion and
recovery in the male hamster. Journal of Comparative and Physio-
logical Psychology, 52, 56-66.
Bielert, C. F. & Goy, R. W. (1973). Sexual behavior of male rhesus:
Effects of repeated ejaculation and partner's cycle stage. Hor-
mones and Behavior, 4, 109-122.
Bunnell, B. N., Boland, B. D. & Dewsbury, D. A. (1976). Copulatory
behavior of golden hamsters (Mesocricetus aurutus). Behavior,
Clark, J. T., Smith, E. R. & Davidson, J. M. (1985). Testosterone is
not required for the enhancement of sexual motivation by
yohimbine. Physiology and Behavior, 35, 5 17-52 1.
Fernandez-Guasti, A. & Escalante. A. (1991). Role of presynaptic
serotonergic receptors on the mechanism of action of 5-HT,,
and 5-HT,, agonists on masculine sexual behaviour: Physiolo-
gical and pharmacological implications. Journal of Neural Truns-
mission (Gen. Sec i. 85, 95-107.
Fernandez-Guasti, A., Escalante, A. & Agmo. A. (1989). Inhibitory
action of various 5-HT,, receptor agonists on rat masculine
sexual behaviour. Phurmacology, Biochemktry and Behavior, 34,
O 2003 The Scandinavian Psychological Associations.
Scand J Psycho1 44 (2003) Download full-text
Sexual exhaustion in male rats 263
Fernindez-Guasti, A., Escalante, A., Ahlenius, S., Hillegaart. V. &
Larsson, K. (1992). Stimulation of 5-HT,, and 5-HT,, receptors
in brain regions and its effects on male rat sexual behaviour.
European Journal of Pharmacology, 210, 121-129.
Fernindez-Guasti, A,, Larsson, K. & Beyer, C. (1986). GABAergic
control of masculine sexual behavior. Pharmacologj: Biochetnis-
try and Belruvior, 24. 1065-1070.
Fernandez-Guasti, A. & Rodriguez-Manzo, G. (1992). Further evidence
showing that the inhibitory action of serotonin on rat masculine
sexual behavior is mediated after stimulation of 5-HT,, receptors.
Pharmacology, Biochemistr~. and Brhcr~iur, 42, 529-533.
Fernandez-Guasti, A. & Rodriguez-Manzo, G. (1997). 8-OH-DPAT
and male rat sexual behavior: Partial blockade by noradrenergic
lesion and sexual exhaustion. Pharmacology, Biochemistry and
Behavior, 56. 11 1- 1 16.
Fernandez-Guasti, A,, Swaab, D. & Rodriguez-Manzo, G. (2003).
Sexual behavior reduces hypothalamic androgen receptor immun-
oreactivity. Ps~rhoneuroendocrinolugy, 28, 501-512.
Fisher, A. E. (1962). Effects of stimulus variation on sexual sati-
ation in the male rat. Journal of Comparative and PIi~~siologic~al
Ps~.chology, 55, 614-620.
Fowler, H. & Whalen, R. E. (1961). Variation in incentive stimulus
and sexual behaviour in the male rat. Journal of Cornpararive and
Pl~~.~iolugicul P.rychology, 54, 68-7 1.
Greco. B., Edwards, D. A., Michael, R. P. & Clancy, A. N. (1996).
Androgen receptor immunoreactivity and mating-induced Fos
expression in forebrain and midbrain structures in the male rat.
Neuroscience, 75, 16 1-1 7 1.
Greco, B., Edwards, D. A,. Michael. R. I? & Clancy, A. N. (1998).
Androgen receptor and estrogen receptors are colocalized in male
rat hypothalamic and limbic neurons that express Fos immuno-
reactivity induced by mating. Neuroendocrinology, 67, 18-28.
Haensel, S. M., Mos, J., Van der Schoot. P. & Slob, A. K. (1993).
Testosterone is required for the stimulatory effects of 8-OH-
DPAT on sexual behavior in castrated male rats. European
Journal of' Phormacology, 233. 187-192.
Hillegaart. V. & Ahlenius, S. (1998). Facilitation and inhibition of
male rat ejaculatory behaviour by the respective 5-HT,, and 5-
HT,, receptor agonists 8-OH-DPAT and anpitroline. as evid-
enced by use of the corresponding new and selective receptor
antagonist NAD-299 and NAS- 18 I. British Journal 01' Phurmu-
eulogy, 125, 1733-1734.
Hsiao, S. (1969). The Coolidge effect in male rat copulatory behaviour:
Failure to replicate Fisher's results. Psychonomic Science, 14. 1-2.
Larsson. K. (1956). Conditioning und sexual behaviour in the male
ulbino rut. Stockholm: Almqvist and Wiksell.
Larsson, K., Fuxe, K., Everitt, B. J., Holmgren, M. & Sodersten, P.
(1978). Sexual behaviour in male rats after intracerebral injec-
tion of 5,7 dihydroxytryptamine. Bruin Research, 141, 293-303.
Lawrence, K. M. & Barfield, R. J. (1975). Differential rates of
exhaustion and recovery of several parameters of male rat sexual
behavior. Journal of C'umpurative und Physiological Psychology,
Mas, M., Fumero. B.. Fernindez-Vera, J. R. & Gonzalez-Mora, J. L.
(1995a). Neurochemical correlates of sexual exhaustion and recovery
as assessed by in vivo microdialysis. Bruin Research, 675, 13-19.
Mas. M.. Fumero, B. & Perez-Rodriguez, I. (1995b). Induction of
mating behavior by apomorphine in sexually sated rats. Euro-
pean Journal of Pharmacology, 280, 33 1-334.
McGinnis, M. Y., Williams, G. W. & Lumia, A. R. (1996). Inhibition
of male sex behavior by androgen receptor blockade in preoptic
area or hypothalamus, but not amygdala or septum. Physiology
and Behavior, 60, 783-789.
Meisel. R. L. & Sachs, B. D. (1994). The physiology of male sexual
behavior. In E. Knobil & J. Neil1 (Eds.), The physiology ufrepro-
duction (pp. 3-105). New York: Raven Press.
O 2003 The Scandinavian Psychological Associations.
Mendelson, S. D. & McEwen, B. S. (1990). Testosterone increases
the concentration of '[HI 8-hydroxy-2-(di-n-propy1amino)tetralin
binding at 5-HT,, receptors in the medial preoptic nucleus of
the castrated male rat. European Journirl 01' Phirrrnircology, 181,
Miller, R. L. & Baum, M. J. (1987). Naloxone inhibits mating and
conditioned place preference for an estrous female in male rats
soon after castration. Pharmacology, Bioc11etni.srr.v and Behavior,
Pfaus, J. G. & Gorzalka. B. B. (1987). Opioids and sexual behavior.
Neuroscience and Biohehovioral Reviews, 11, 1-34.
Phoenix, Ch. H. & Chambers, K. C. (1988). Old age and sexual
exhaustion in male rhesus macaques. Physiology and Behavior.
Qureshi, G. A. & Sodersten, P. (1986). Sexual activity alters the
concentration of amino acids in cerebrospinal fluid of male rat.
Neuro.~cience Lerrers, 70, 374-378.
Rodriguez-Manzo, G. (1999a). Yohimbine interacts with the
dopaminergic system to reverse sexual satiation: Further evidence
for a role of sexual motivation in sexual exhaustion. Europeim
Journal of Pharmacology, 372, 1-8.
Rodriguez-Manzo, G. (1999b). Blockade of the establishment of the
sexual inhibition resulting from sexual exhaustion by the
Coolidge effect. Behavioural Brain Re.rc~tzrch. 100, 245-254.
Rodriguez-Manzo, G., Asai, M. & Fernandez-Guasti, A. (2002a).
Evidence for changes in brain enkephalin contents associated to
male rat sexual activity. Behavioural Bruin Rcwarch. 131, 47-55.
Rodriguez-Manzo, G. & Fernindez-Guasti, A. (1994). Reversal of
sexual exhaustion by serotonergic and noradrenergic agents.
Brhirvioural Brain Reseurch, 62, 127-134.
Rodriguez-Manzo, G. & Fernindez-Guasti, A. (1995a). Opioid
antagonists and the sexual satiation phenomenon. Psychophcrr-
mucologj, (Berlin). 122, 131-136.
Rodriguez-Manzo, G. & Fernandez-Guasti, A. (1995b). Participa-
tion of the central noradrenergic system in the reestablishment
of copulatory behaviour of sexually exhausted rats by yohim-
bine, naloxone, and 8-OH-DPAT. Bruin Reseurch Bulletin, 38,
Rodriguez-Manzo, G., Lopez-Rubalcava. C., Hen, R. & Fernindez-
Guasti, A. (2002b). Participation of 5-HT,, receptors in the
inhibitory actions of serotonin on masculine sexual behaviour of
mice: Pharmacological analysis in 5-HT,, receptor knockout
mice. British Journal of Plzurrnucolog~~.
Rodriguez-Manzo, G., Pellicer, F.. Larsson, K. & Fernandez-
Guasti, A. (2000). Stimulation of the medial preoptic area facil-
itates sexual behaviour but does not reverse sexual satiation.
Behavioral Neuroscience, 114. 553 -560.
Rowland, D. L. & Houtsmuller, E. J. (1998). 8-OH-DPAT interacts
with sexual experience and testosterone to affect ejaculatory
response in rats. Pharmacology, Biochemistry and Behavior, 60,
Salis. P. J. & Dewsbury, D. A. (1971). P-Chlorophenylalanine facil-
itates copulatory behaviour in male rats. Nature. 232. 400-401.
Verma, S., Chhina, G. S., Mohan Kumar, V. & Singh. B. (1989).
Inhibition of male sexual behavior by serotonin application in
the medial preoptic area. Physiology and Behavior, 46, 327-330.
Wilson, J. R., Kuehn, R. E. & Beach, F. A. (1963). Modification in
the sexual behaviour of male rats produced by changing the
stimulus female. Journal of Comparative und Physiological Psy-
chology, 56, 636-644.
Yells, D. P., Hendricks, S. E. & Prendergast, M. A. (1992). Lesions
of the nucleus paragigantocellularis: Effects on mating beha-
viour in male rats. Bruin Rt~sc~irrch,
Zucker, I. & Wade, G. (1968). Sexual preferences of male rats.
Journal of Comparative and Physiological Psychology, 66, 816-
136. 1127-1 134.