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mise à jour du
8 septembre 2002
European J of Neuroscience 2002;15:852-860
lexique
Reduction of drug-induced yawning and penil erection and of noncontact erections in male rats by the activation of GABAa receptors in the paraventricular nucleus: involvement of nitric oxide
MR Melis, A Argiolas
 
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

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Several neurotransmitters and neuropetides are involved at the level of the paraventricular nucleus of the hypothalamus (PVN) in the control of yawning and penil erection that occurs in ex-copula and in-copula conditions. Accordling, oxytocin, D2 dopamine receptor agonists and NMDA induce penile erection and yawning when injected into the PVN of freely moving rats. Also, D2 receptor agonists injected into the PVN modulate genital reflexes in restrained male rats and during copulation. The behavioural effects observed after injection of D2 receptors agonists NMDA and oxytocininto the PVN may be secondary to the activation of a group of oxytocinergic neurons that originate in the PVN and project to extrahypothlamic brain areas, and/or, as far as for penile erection is cocerned, to the spinal lumbosacral nucleus of the bulbospongiosum and to the penis. The facilitative effects of dopamine receptor agonists. NMDA and oxytocin on penile erection and yawning are apparently mediated by an increased production of nitric oxide (NO) in the cell bodies of these oxytocinergic neurons. Accordingly, NO donors injected into the PVN induce penile erections and yawns, that are indistinguishable from those induced by the above compounds, by activating central oxytocinergic transmission. Finaly dopamine receptor agonist, oxytocin and NMDA induce penile erection and the concomitant increase in NO production in the PVN can be prevented by the opiate morphine injected into the PVN in a naloxone-dependent manner.

Mechanisms similar to those described above seem to operate in the PVN when penile erection occurs in physiological contexts., eg during non contact erections and copulation. Noncontact erections and steroid dependenterections, mediated by volatile pheromones, which occur sexually potent mal rats exposed to an inaccessible receptive female, and are considered a model for investigating the neural mediatin of sexual arousal. several lines of experimental evidence support this hypothesis. First vasotencin, given into lateral ventricles, not only prevents drug and oxytocin-induced penile erection, but also prevents noncontact and impairs copulation. Second, NO production is increased in the PVN during noncontact erections and copulation and this increase is prevented by the NO synthase inhibitor nitro-L-arginine methylester, by morphine or by the NMDA receptor antagonist. MK-801, injected into the PVN at doses that also prevent noncontact erections and copulation.

We have recently found that the activation of GABAA receptors, by Muscirnol, in the PVN prevents both penile erection and yawning induced by the mixed D1/D2, receptor agonist, apomorphine, and by oxytocin and NMDA and also noncontact penile erections. These findings are in line with immunocytochemical and electrophysiological studies showing that paraventricular magnocellular and parvocellular oxytocinergic neurons are under inhibitory GABAergic control and suggest that GABA is also involved at the PVN level in the control of penile erection and yawning. Accordingly, GABA synapses impinge on the cell bodies of oxytocinergic neurons, and GABA agonists decrease oxytocinergic transmission in several circumstances. The majority of these inhibitory synapses belong to GABAergic neurons originating mainly in the perinuclear region that surrounds the PVN, although the presence of intraparaventricular GABAergic neurons cannot be ruled out. To further characterize the role of GABA, at the level of the PVN, in the control of yawning and penile erection, we studied the effect of muscimol on the increase of paraventricular NO production that occurs concomitantly with penile erection and yawning induced by apornorphine, oxytocin and NMDA as well as during noncontact penile erections. [...]

Discussion

The present results confirm and extend previous studies showing that muscimol, a GABAa receptor agonist, but not baclofen, a GABAb receptor agonist, delivered into the PVN reduces penile erection and yawning induced by apomorphine, oxytocin or NMDA in male rats. Of particular importance is the finding that this inhibitory effect of muscimol occurs together with a concomitant reduction of the NO,and N03- increase usually found in the paraventricular dialysale when these behavioural responses are induced by the above compounds. As baclofen, which is several times more active than muscimol on GABAb receptors, is unable to prevent these responses, and the musciniol effect is abolished by bicuculline, a GABAa receptor antagonist, muscimol apparently reduces penile erection, yawning and the paraventricular N02- and N03- increase induced by the above compounds by stimulating GABAa receptors in the PVN. As penile erection and yawning are apparently mediated by the activation of NO synthase present in paraventricular oxytocinergic neurons projecting to extrahypothalainic brain areas, which mediate these behavioural responses, it is likely that these GABAa receptors are located on the cell bodies of these oxytocinergic neurons (see above). As GABAergic synapses impinge on parvocellular and magnocellular oxytocinergic neurons, the finding suggests that GABAergic synapses also impinge on and control (in an inhibitory fashion) oxytocinergic neurons mediating penile crection and yawning by interfering with the mechanisms activated by apomorphine, oxytocin and NMDA, which lead to the activation of NO synthase. As expected, muscimol reduces not only penile erection and yawning but also the paraventricular NO2- and N03 increase induced by NMDA at doses lower than those required to reduce these responses induced by oxytocin and apomorphine.

This higher sensitivity of NMDA-induced activation of oxytocinergic neurons mediating penile erection and yawning to GABAergic inhibition when compared to that induced by apomorphine and oxytocin, may be due to the fact that muscimol acts not only on GABAa receptors located in the cell bodies of oxytocinergic neurons to inhibit their activation by NMDA, apomorphine or oxytocin, but also on GABAergic receptors that control an endogenous excitatory, (possibly glutamatergic) input to oxytocinergic neurons. This would cause, in turn, a decrease in the release of endogenous glutamic acid, thereby producing a more pronounced inhibition of oxytocinergic neurons, which renders them less sensitive to injected exogenous NMDA.

In line with this hypothesis, excitatory glutamatergic synapses impinge on paraventricular oxytocinergic neurons. Altematively, the higher doses of muscimol required to reduce apomorphine and oxytocin responses, when compared to NMDA responses, may simply reflect the different molecular mechanisms mediating apomorphine- oxytocin- and NMDA-induced penile erection and yawning. Namely, although a Ca2+ influx apparently mediates NMDA-, apomorphine and oxytocin-induced penile erection, yawning and the paraventricular NO2- and N03- increase, NMDA induces these responses by acting on NMDA receptorcoupled, voltage-dependent Ca 2+ channels, while apomorphine and oxytocin activate conotoxin-GVIA-sensitive Ca2+ channels. Whatever mechanism may be responsible for the different sensitivity to muscimol of NMDA, oxytocin and apomorphine responses, muscimol prevents penile erection, yawning and paraventricular NO2- and NO3- increase induced by all the above compounds, suggesting that GABA exerts an inhibitory control on oxytocinergic neurons mediating these responses, as found with other oxytocinergic neurons. Accordingly, GABA inhibits oxytocin release induced by suckling and by osmotic stimuli.[...]