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26 décembre 2002
Pharmacol BiochemBehav 1997; 58; 2; 291-298
GABAergic drugs and socio-sexual behavior
Paredes RG, Karam P, Highland L, Agmo A
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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