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mise à jour du
31 mars 2005
1997; 36, 6; 769-777
Involvement of dopamine D2 receptors in the effect of cocaine on sexual behaviour and stretching-yawning of male rats
F Ferrari, D Giuliani
Department of Biomedical Sciences, Division of Pharmacology, University of Modena, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Cocaine abuse is a major public health problem. The drug has a reputation as an enhancer of sexual drive, performance and pleasure and is frequently used for these purposes. The sexualstimulant properties of cocaine are not surprising, as one of the major actions of the drug is to block the reuptake of dopamine (DA) and so increase its synaptic availability; also the key role of DA in modulating reward and sexual behaviour is well documented. However, there are few properly-controlled studies relating cocaine effects to human and animal sexual behaviour. Since animal models have proved to be valid tools in the evaluation of cocaine activity, our study was first designed to examine the influence of cocaine on three different aspects of male rat sexual behaviour.
We took into account: (1) penile erection (PE) of sexually-naive animals in the absence of females in oestrus (2) copulatory performance of sexually-experienced rats; and (3) indiscriminate mounting stimulated by the dopaminergic agonist, lisuride. In order to investigate the involvement of DA D2 receptors in the effects of cocaine on sexual behaviour, some tests were conducted after the pretreatment of rats with the selective DA D2 antagonist, (-) eticlopride, which is reported to interfere with DA agonist-induced PE and stereotyped behaviour in rats. Further, a series of experiments was performed to evaluate the stretching-yawning (SY) response to the challenge of the DA D2 agonist, SND 919, at a low, non-stereotyping dose in rats subchronically-treated with cocaine.
The rationale behind this investigation is that neurochemical alterations at DA ergic levels brought about by repeated injections of cocaine might involve the DA D2 autoreceptor function, and might be reflected in a modified SY response. This is reputed by many researchers to be an index of the stimulation of DA D2 autoreceptors. However, others believe that the DA receptors involved in SY are post-synaptically located; they would be DA sensitive as autoreceptors and might correspond to DA D3 receptors.
The present study confirms the stimulant properties of acute cocaine on PE in freely moving rats in the absence of receptive females and provides new information about the influence of the drug on the copulatory pattern of male rats and on some of the behavioural effects induced by DA agonists. Previous experiments in our laboratory described cocaine-induced PE at a dose (15 mg/kg) that is now reported to be ineffective. The reason for this discrepancy probably lies in the different methods used (strain of animals and adaptation period in the test cages before cocaine injection), with repercussion on the animals' motor activity, which seems markedly to inhibit PE. However, the influence exerted by the DA D2 antagonist (-) eticlopride on cocaine-induced effects is confirmed: while (-) eticlopride antagonized cocaine-induced motor hyperactivity it did not inhibit PE which, in the case of high cocaine doses, was actually stimulated. This finding is in accordance with those of other studies where the DA D2 antagonist has been found to counteract behavioural sensitization to cocaine-induced motor hyperactivity and to reverse the inhibitory effect of cocaine on PE observed after repeated injections with the stimulant.
Acute injection of cocaine at moderate doses facilitated indiscriminate mounting, typically elicited by lisuride at doses higher than 0.2 mg/kg . The term "indiscriminate" is justified, as in preliminary experiments conducted in our laboratory it was seen that males treated with lisuride indiscriminately mounted males or females in oestrus or not, all grouped together, and that cocaine pretreatment does not affect sexual preference (data not presented). Facilitation of the phenomenon was prevented by pretreatment with (-) eticlopride, as was motor hyperactivity, thus suggesting that DA D2 mediated mechanisms are crucially involved in both behaviours but are not those underlying PE. Moreover, results obtained after (-) eticlopride are in line with those reporting the antagonism exerted by classical neuroleptics towards heightened locomotor activity after cocaine and suggest that indiscriminate mounting is likely to be a form of compulsive motor induction rather than motivated sexual stimulation.
As regards the mating tests, the most striking effect after acute cocaine injection at 7.5 and 15 mg/kg was the increase in mounts preceding ejaculation. In human terms, such a result, along with acute cocaine-induced PE could suggest an enhancement of sexual appetitive behaviour and, therefore, an aphrodisiac-like effect of the drug. Alternatively, an increase in mounts before ejaculation could be interpreted as a decrement in copulatory behaviour, whereby the rats need more stimulation in order to ejaculate. In the light of the overall data obtained, it is hardly likely that cocaine has a consistent and, above all, long-lasting sexual stimulant effect on male rats. It is well known that the copulatory behaviour of these animals comprises a precopulatory phase, the most common measure of which is ML, and a consummatory phase, mainly represented by IF and EL. While ML as well as PET are considered indexes of rat sexual appetitive behaviour, IF and EL reflect the ejaculatory threshold; sex arousal and ejaculatory mechanisms are distinct, as demonstrated by the different influence of drugs on the respective parameters. In our study, neither acute nor subchronic cocaine at 15 mg/kg was able to stimulate copulatory behaviour in SI rats; moreover, cocaine at 7.5 and 15 mg/kg did not significantly reduce the IL, ML and PET of SA rats but actually prolonged them dramatically when administered acutely at 30 mg/kg, when there was a general abatement of sexual activity, reflected in all the other test parameters.
The impairment of copulatory ability was aggravated by subchronic treatment of cocaine and was long-lasting, for even after treatment had been suspended for a week the animals' performance was still markedly impaired. Despite the fact that our tests were conducted during the light phase, it seems improbable that the effects obtained after cocaine are dependent on the experimental procedure adopted, for although rats are nocturnal animals, it has been found that after appropriate training, copulatory tests are regularly performed in the light phase by a high percentage of animals. The increase in MF produced by acute cocaine at moderate doses was completely abolished by 7 days of treatment, thus suggesting that this effect declines rapidly, as in the case of PE. The mating pattern observed in rats after subchromc cocaine, in particular at 15 mg/kg, differed significantly from that obtained after the first injection and shows that only ejaculation mechanisms are affected; moreover, it seems to reflect a premature ejaculation reminiscent of that produced by acute systemic DA agonists.
This similarity between subchronic cocaine- and DA agonist-induced effects would, therefore, suggest that the neuronal substrates in the two cases are quite similar, though different from those affected by acute cocaine injection. The role of the specific DA receptors involved in the facilitation of ejaculation by DA agonists is questioned. What is more, any hypothesis as to the mechanisms involved in the various behavioural effects exerted by such compounds now seems suspect in view of the proliferation of DA receptor subtypes and of the yet limited understanding of specific affinity for them of the DA agonists and antagonists. (-) Eticlopride, itself previously described as a selective DA D2 antagonist, has more recently been reported as having considerable affinity for the DA D3 receptor.
However, leaving aside any specific neurochemical interpretation of the effects of cocaine on rat sexual behaviour, our findings support the notion that, although the drug might heighten sexual potency and urge in the short term (hence its popular reputation as one of the best aphrodisiacs), after high doses or repeated use it may well have an inhibitory effect. In fact, just as drug-induced hyperactivity sensitizes , certain sexual stimulant effects rapidly decline. A functional as well as neurochemical interdependence of the two phenomena is possible and would also be indirectly confirmed by the results obtained on cocaine-induced PE and motor activity after (-) eticlopride pretreatment.
There is conflicting evidence regarding DA D2 autoreceptor function after chronic cocaine some authors have found a decrease, some an increase and others no change. The present study clearly shows a significant enhancement of SND 919-induced SY after 7 days of cocaine treatment. If it is true that the SY syndrome reflects the selective stimulation of DA D2 autoreceptors or DA D3 receptors, our behavioural results would indirectly confirm that one of these two DA receptor subtypes is supersensitive, at least in our experimental conditions. Since a DAergic deficit is the result of stimulation both of DA D2 autoreceptors, which inhibit DA synthesis and release, and of DA D3 receptors, our data are in accordance with those showing DA depletion after chronic use of cocaine. However, in view of the fact that cocaine blocks the reuptake of monoamines in general, clarification of this issue awaits the result of further biochemical and behavioural studies.