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mise à jour du 26 décembre 2002
Neurosci Lett
2000; 281; 2-3; 127-30
lexique
Activation of gamma-aminobutyric acid(A) receptors in the paraventricular nucleus of the hypothalamus reduces apomorphine-, N-methyl-D-aspartic acid- and oxytocin-induced penile erection and yawning in male rats
Melis M, Spano MS, Succu S, Argiolas A
Department of Neuroscience, University of Cagliari, Cagliari
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

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Penile erection and yawning are two different behavioral patterns that often occur concomitantly in different experimental and physiological conditions. While the importance of penile erection in mammalian reproduction does not need to be stressed, it is pertinent to recall that yawning is considered an ancestral vestige that subserves the purposal of arousal, although its role is far from being clarified.
 
Among substances that induce both penile erection and yawning in male rats, the best known are dopamine receptor agonists, such as apomorphine, the neurohypophyseal peptide oxytocin, N-methyl-D-aspartic acid (NMDA), a selective agonist of the excitatory amino acid NMDA receptor subtype, and adrenocorticotropic hormone (ACTH) - melanocyte stimulating hormone (MSH) peptides. Apomorphine, NMDA and oxytocin induce penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus (PVN), apparently by activating parvocellular oxytocinergic neurons originating in the PVN and projecting to extra-hypothalamic brain areas (e.g. the hippocampus, the medulla oblongata and the spinal cord), while ACTH-MSH peptides induce the above responses by acting with a different mechanism. The induction of penile erection and yawning by the above substances is secondary to the activation of nitric oxide synthase activity in the PVN, possibly in the cell bodies of oxytocinergic neurons mediating penile erection and yawning. Accordingly, nitric oxide production is increased in the PVN by doses of apomorphine, oxytocin or NMDA that induce penile erection and yawning.
Immunocytochernical and electrophysiological studies show that paraventricular magnocellular and parvocellular oxytocinergic neurons are under inhibitory GABAergic control. Accordingly, gamma-aminobutyric acid (GABA) synapses impinge on the cell bodies of oxytocinergic neurons, and GABA agonists decrease oxytocinergic transmission in several circumstances. The major ty 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. The presence of GABAergic synapses impinging on oxytocinergic neurons raises the possibility that GABAergic agents might influence penile erection and yawning, at the PVN level.
 
To test this hypothesis we studied the effect of muscimol, an agonist of the GABAA receptor, and baclofen, an agonist of the GABAB receptor, injected into the PVN, on apomorphine-, oxytocin- and NMDA-induced penile erection and yawning. [...]
As found in previous studies, apomorphine (50 ng), oxytocin (10 ng) or NMDA (50 ng) injected into the PVN induced repeated penile erection and yawning episodes when compared to vehicle (saline. Muscimol (50-200 ng) reduced dose-depenilently penile erection and yawning induced by apomorphine, oxytocin or NMDA when injected into the PVN 10 min before the above compounds. Muscimol effect on NMDA-induced penile erection and yawning was seen already at the dose of 50 ng, which reduced NMDA responses by more than 50%, while a dose of 100 ng was required to reduce oxytocin and apomorphine responses by the same extent. The maximal effect on NMDA responses was found with 100 ng, while 200 ng were necessary to reduce apomorphine and oxytocin responses almost completely. In contrast, baclofen (200 ng) was unable to reduce penile erection and yawning induced by apomorphine, oxytocin and NMDA when injected into the PVN 10 min before these compounds. At the doses injected into the PVN, muscimol and baclofen did not induce penile erection, yawning or any visible gross behavioral change or motor disturbances (not shown).
Fig. 2 shows that bicuculline (250 ng) prevents the reduction by muscimol of penile erection and yawning induced by apomorphine, oxytocin and NMDA, when injected into the PVN 5 min before muscimol (100 ng). At the dose injected into the PVN, bicuculline did not induce penile erection, yawning or any gross behavioral change (not shown).
The present results show that muscimol, a GABAA receptor agonist, but not baclofen, a GABAB receptor agonist, given into the PVN reduces penile erection and yawning induced by apomorphine, oxytocin or NMDA. Since baclofen, which is several times more active than muscimol on GABAB receptors, is unable to prevent these responses, and muscimol effect is abolished by bicuculline, a GABAA receptor antagonist, muscimol apparently reduces penile erection and yawning induced by the above compounds by stimulating GABAA receptors in the PVN.
 
It is likely that these GABAA receptors are located in the cell bodies of paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas, which mediate these behavioral responses (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 erection and yawning.
 
Surprisingly, muscimol reduced penile erection and yawning induced by NMDA at doses lower than those required to reduce the above responses induced. by oxytocin and apomorphine. This indicates that the activation of oxytocinergic neurons mediating penile erection and yawning by NMDA is more sensitive to GABAergic inhibition than the activation by apomorphine or oxytocin. One possibility is 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 endogenos 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 makes them less sensitive to the injected exogenous NMDA. In line with this hypothesis excitatory glutamatergic synapses impinge on paraventricular oxytocinergic neurons. Alternatively, the higher doses of muscimol required to reduce apomorphine and oxytocin responses, when compared to NMDA responses, might simply reflect the different molecular mechanisms mediating apomorphine- oxytocin- and NMDA-induced penile erection and yawning.
 
Namely, although a Ca 2+ influx apparently mediates NMDA-, apomorphine and oxytocin-induced penile erection and yawning, NMDA induces these responses by acting on NMDA receptor-coupled voltagedepenilent Ca 2+ channels, while apomorphine and oxytocin activate (-conotoxin-GVIA-sensitive Ca 2+ channels. Whatever mechanism may be responsible for the different sensitivity to muscimol of NMDA, oxytocin and apomorphine responses, muscimol prevents penile erection and yawning 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. Whether the ability of muscimol to reduce penile erection and yawning reflects a physiological role of GABAA receptors at the PVN level in these behavioral responses cannot be decided from the present results. Indeed, in our experimental conditions control rats show very low values of penile erection and yawning, making it impossible to detect an inhibitory effect of muscimol on spontaneous penile erection and yawning in these animals. However, as bicuculline, which blocks GABAA receptors, is unable per se to induce penile erection and yawning when injected into the PVN, paraventricular GABAergic synapses that control oxytocinergic neurons mediating these behavioral responses are apparently not tonically active.
 
Although GABA is the major inhibitory neurotransmitter in the brain, its role in the control of penile erection and yawning is poorly understood. In agreement with our results, it has been recently reported that muscimol given systemically reduces penile erection induced by apomorphine [20], and that GABA agonists reduce penile reflexes induced in restrained male rats after retraction of the penile sheath [5] and impair copulation [5,9,141. However, in contrast with the present results, these studies also reported that baclofen given systemically reduces'penile erection induced by apomorphine [201 and penile reflexes in restrained male rats, apparently by acting in the lumbosacral spinal cord. Baclofen was also found able to reduce yawning in two sublines of rats showing high and low spontaneous yawning frequency. This discrepancy may be due to several reasons. Firstly, the majority of studies quoted above, like many other studies in which GABAergic drugs are given systemically, are complicated by the often dramatic sedative effects of these compounds. This causes severe motor disturbances that interfere with many behaviors, making it impossible to clarify a specific role of GABA in the responses studied. Secondly, GABAergic drugs given systemically reach all brain structures, and the observed effect is the algebraic sum of the actions induced by these compounds at all reached sites. In particular, GABAergic stimulation of GABAA and GABAB receptor might produce different, e.g. inhibitory or excitatory, effects on yawning and penile erection, depending on the brain area in which they act. Although further studies are necessary to clarify the mechanism(s) by means of which GABA receptor agonists influence penile erection and yawning, this study shows for the first time that GABAA receptors are involved in the qontrol of penile erection and yawning at the PVN level.
 
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