Escuela de psicologia,
Universidad Anahuac, Mexico
Male sexual behavior is among the many
behaviors modified by GABA. The observation that
the concentration of GABA in the cerebrospinal
fluid of male rats significantly increases after
ejaculation may suggest that GABA is related to
the postejaculatory behavioral inhibition. In
support of this hypothesis, it was reported that
infusion of the GABAA agonist muscimol and the
GABA transaminase inhibitor
ethanolamine-0-sulphate into the medial preoptic
area (MPOA) produced strong inhibition of most
aspects of sexual behavior. In contrast,
infusion of GABAA antagonists into the MPOA
facilitated sexual behavior in castrated
testosterone-treated rats, reduced the duration
of the ultrasonic vocalizations that are
normally emitted by the male rat after
ejaculation, and shortened the postejaculatory
interval. However, direct infusion of GABA had
litde effect on copulation, producing only a
slight increase in intromission latency.
Moreover, the facilitatory effects on
pre-ejaculatory parameters, Le.,
interintromission interval and ejaculation
latency, observed in the same study do not agree
with a role for GABA in only postejaculatory
events. In fact, a facilitation of sexual
behavior similar to that produced by infusion of
GABAA antagonists bas been observed shortly
after an electrolytic lesion of the MPOA, giving
no clear evidence for a role of the GABAA
receptor in the control of male sexual behavior.
Rather, it seems that any enhancement of
activity within the MPOA stimulates male sexual
behavior.
The role of GABA receptor subtypes in sexual
behavior has been analyzed in previous
pharmacological studies. The systemic
administration of the GABAA agonist
4,5,6,7-tetrahydroisoxazolo[5,4c]-pyridin-3-ol
(THIP) inhibits sexual behavior. However, the
inhibitory effects of THIP were not blocked by
concurrent administration of bicuculline;
another GABAA agonist, 3-aminopropanesulfonic
acid (APSA), had no effect on sexual behavior.
These data further support the hypothesis that
the GABAA receptor is not involved in the
control of male sexual behavior.
The enhancement of GABAergic
neurotransmission produced by GABA transaminase
inhibitors (GTIs) also inhibits sexual
behavior in the male rat. However, a
detailed behavioral analysis has shown that the
inhibitory effects produced by GTIs are
associated with strong motor deficiencies, ie.,
sexual behavior is inhibited only at doses at
which motor execution is much impaired.
Furthermore, this class of drugs reduces the
intromission ratio, thereby suggesting
difficulties in achieving penile insertion.
However, GTIs did not disturb the copulatory
thrusting pattern that allows the penis to find
the vaginal orifice. Rather, GTIs appear to
reduce the duration of contraction of the
ischiocavernosus muscles in copula. The
contraction of these muscles is necessary for
penile insertion.
The stimulation of GABAB receptors by
baclofen inhibits penile reflexes ex copula and
sexual behavior in doses not associated with an
impairment of motor execution. The inhibitory
effects on sexual behavior produced by baclofen
are blocked by concurrent administration of the
GABAB antagonist CGP35348 (32). It has also been
reported that baclofen inhibits precopulatory
and copulatory behaviors in male rats without
affecting nonsexual social interactions or
exploratory behaviors. It appears, then, that
stimulation of the GABAB receptors has a
specific inhibitory effect on behaviors
associated with the initiation of copulatory
activity.
To further understand the complex role of
GABA in the control of sexual behavior, a
detailed analysis is required. In the present
experiment, copulatory parameters as well as
exploratory behaviors and sociosexual
interactions with a castrated male and a
receptive female were evaluated in male rats
after: a) specific stimulation of GABAA
receptors, b) enhancement of GABA levels by
administration of GTIs, and c) reduction of GABA
concentrations by inhibition of the synthesis of
this neurotransmitter. If drug effects were
similar in social interactions with a castrated
male and sexual interactions with a receptive
female, it could be argued that a generalized
behavioral impairment is produced. If the
effects were observed only when the animals are
tested with a receptive female, they could be
specifîc to sexual behavior. The
behavioral specificity of the drug actions was
further analyzed in a free drinking procedure.
In that way, it could be determined if the drugs
that inhibited sexual behavior also reduced
another biologically relevant behavior.
[...]
Discussion : We have previously
suggested that some GABAergic drugs affect
sexual behavior only inderectly, via an
impairment of motor execution. The results
from the present experiment support and extend
this hypothesis. The effective doses reduce
ambulatory activity and frequently also motor
coordination, as evaluated by open field
activity and a treadmill test in this
laboratory. However, it is not certain that a
motor impairment can explain all behavioral
effects of the drugs. The reduction of sexual
behavior was always associated with reduced
social interactions and exploratory
behaviors. This could suggest that the drugs
have a general inhibitory action on behavior,
perhaps independent of their motor effects,
reducing sensitivity to environmental stimuli.
The results of the licking experiment suggest
that this reduced sensitivity is not specific to
sexually relevant stimuli. Even such a powerful
incentive as water lost its capacity to activate
the appropriate behavior in water-deprived rats
after treatment with the drugs in doses that
inhibited sexual behavior.
Effects similar to those reported here have
previously been found with dopamine antagonists.
These drugs reduce sexual behavior and
ambulatory activity and induce motor
incoordination, in addition to inhibiting
exploratory behavior. To explain these effects,
it was suggested that dopaminergic activation
is permissive to the initiation of sexual
behavior. This proposal is supported by
recent data showing that rats that copulate
shortly after castration, in contrast to
noncopulating rats, release dopamine in the
medial preoptic area in response to a receptive
female. There is extensive evidence showing that
enhanced GABAergic activity inhibits
dopaminergic systems. It is possible that
the similar effects of GABAergic agents and
dopamine antagonists are the result of a common
action. Interestingly, large doses of dopamine
antagonists also inhibit drinking in thirsty
rats.
Unfortunately, this explanation does not
apply to the effects of GABA synthesis
inhibitors. We have previously reported that
picrotoxin, in subconvulsive doses, also
inhibits male sexual behavior, whereas no effect
was obtained with bicuculline. There is also
evidence showing that some GABA agonists and
antagonists have simlar effects on ambulatory
activity, motor coordination, and analgesia.
Some studies have also found that baclofen has
proconvulsive effects. Currently, no convincing
explanation is available, but it can be
speculated that any modification of GABAergic
activity outside the physiological range
disrupts neuronal functioning.
The only GABAergic drug tested so far that
inhibits sexual interactions without modifying
social or exploratory behaviors is the GABAB
agonist baclofen. Males treated with baclofen
spend significantly less time pursuing the
female and hence do not engage in copulatory
behavior. Pursuit of the female is a crucial
component of sociosexual interactions, allowing
the male to pass from the precopulatory to the
copulatory phase. Male rats with lesions of the
medial preoptic area, a brain structure involved
in the control of male sexual behavior, showed
reduced pursuit of the female and did not engage
in sexual behavior. These effects are strikingly
similar to those found after baclofen treatment.
It might be possible to propose that this drug
modifies activity in the preoptic area.
Indeed, in the female rat, it has been
reported that systemic baclofen much reduces
serotonin (5-HT) turnover in this area; at the
same time, noradrenaline function was much
increased. The biochemical changes observed in
that study were closely correlated with the
appearance of lordosis behavior. This does not
mean, of course, that the effects of the
systemically administered drugs are limited to
the preoptic area. Because baclofen is the only
GABAergic compound that has a specific effect
upon sexual behavior, it could be argued that
the GABAB receptor is directly involved in the
mechanisms that control the initiation of that
behavior. However, a GABAB antagonist bas been
reported to be without effect on male sexual
behavior. This observation makes the
physiological significance of the GABAB receptor
in the control of sexual behavior
uncertain.
As described in the introduction, the
behavioral effects observed after baclofen
administration are most probably mediated by the
GABAB receptor, because they are stereospecific
and blocked by the GABAB antagonist CGP35348. In
contrast, neither the inhibitory effects
observed on sexual behavior after administration
of GABAA agonists nor those of GABA transaminase
inhibitors on locomotor activity were blocked by
bicuculline, suggesting that the GABAA receptors
are of slight importance in the control of
ambulatory activity and sexual behavior.
Pharmacological and behavioral studies
suggest the existence of GABA receptor sites
different from the GABAA and GABAB receptors.
For example, the GABA uptake inhibitor SKF89976A
alone produced a higher antinociceptive response
than did specific stimulation of the GABAA or
GABAB receptors by THIP or baclofen or by
combined treatment with the two agonists (38).
Similarly, SK-F-89976A and y-vinyl GABA had an
anticonvulsant effect, whereas THIP and baclofen
lacked any protective effect against
pentylenetetrazolinduced seizures (38). It is
possible, then, that some of the behavioral
effects of GABAergic compounds observed in the
present study might be mediated by GABA
receptors different from the GABAA or GABAB
sites. Further studies combining drugs that
increase GABA levels (e.g., GTIs) and compounds
that specifically block the different GABA
receptors, as well as studies in which GABA
levels are reduced in combination with specific
GABA receptor agonists, are required to fully
understand the contribution of each receptor
subtype when GABA levels are altered. Clearly,
much additional work is needed before a complete
understanding of the effects of systemically
administered GABAergic agents can be
gained.
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