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mise à jour du 28 août 2003
Naunyn-Schmiedeberg's arch Pharmacol
1995; 351; 439-445
Role of nitric oxide in penile erection and yawning induced by 5-HT1c receptor agonists in male rats
Marla Rosaria Melis, Roberto Stancampiano, Antonio Argiolas
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Introduction : Penile erection and yawning are two distinct behavioral patterns that often occur concomitantly under certain physiological and experimental conditions. Penile erection is a primary sexual response in mammals, including humans, its achievement being essential for the success of reproduction. As to the physiological significance of yawning. it is pertinent to recall that yawning is considered to be an ancestral vestige surviving throughout evolution that subserves the purpose of arousal. Among substances that induce both penile erection and yawning, dopamine receptor agonists (i.e. apomorphine), oxytocin, adrenocorticotropin (ACTH) and N-methylD-aspartic acid (NMDA) are certainly the most widely known.
However, it was recently shown that penile erection and yawning can also be induced in male rats by drugs that modify serotonin (5-HT) transmission, in particular 5-HT receptor agonists that act on the 5-HT, receptor subtype, such as 1-(3-chlorophenyl)-piperazine (m-CPP) and N-(3-trifluoromethylphenyl)-piperazine (TFMPP)
Accordingly, 5-HT1c receptor agonist-induced penile erection and yawning are prevented by 5-HT antagonists with a potency that is parallel to their potency in blocking the 5-HT1c receptor subtype. As to the mechanism(s) responsible for the induction of these behavioral responses by 5-HT1c receptor agonists, very little information is available at present. Briefly, these compounds seem to act by mechanisms different from those that are activated by dopaminergic agonists and oxytocin. Indeed m-CPP or TFMPP induced penile erection and yawning are prevented neither by the dopamine receptor antagonist haloperidol nor by the oxytocin receptor antagonist d(CH2)5Tyr(Me)2-Orn8-vasotocin, nor iliese 5-HT1c receptor agonists induce penile erection and yawning when injecied in the paraventricular nucleus of the hypothalamus (PVN), unlike dopamine agonists or oxytocin. We report here that m-CPP- and TFMPP induced penile erection and yawning, are prevented by the intracerebroventricular (i.c.v.) administration of Ng-nitro-L-arginine methyl ester (NAME) and Ng-monomethyl-L-arginine (NMMA), inhibitors of nitric oxide (NO) synthase, the enzyme responsible for the formation of NO, a novel discovered neutrotransmitter - neuromodulator in the peripheral and central nervous system. Since guanylate cyclase is one of the major targets of NO, the effect of guanylate cyclase inhibitors and NO scavengers on m-CPP- and TFMPP-induced penile erection and yawning is also reported. [...]
Discussion :
The present results show that penile erection and yawning induced by m-CPP and TFMPP, two 5-HT1c receptor agonists, are prevented by NAME and NMMA given i.c.v. at doses insufficient to act peripherally with a potency that is parallel to their potency in inhibiting NO-synthase, the calmodulin-dependent iron-containing enzyme that forms the novel discovered neurotransmitter/neuromodulator NO in peripheral and central neural tissues from L-arginine.
The finding suggests that endogenous NO is involved in the expression of these behavioral responses induced by 5-HT1c receptor agonists. In agreement with this hypothesis, the inhibitory effect of NAME on m-CPP- and TFMPP-induced penile erection and yawning is prevented by the simultaneous excess administration of the precursor of NO L-arginine, which per se did not alter m-CPP and TFMPP responses. Together these findings are in line with previous studies showing that central NO is involved in the control of spontaneous or drug-induced penile erection and yawning. Accordingly,
  1. NO-synthase inhibitors prevent these behavioural responses by the dopaminergic agonist apomorphine, oxytocin and NMDA when injected in the PVN, that contains one of the highest concentrations of NO-synthase in brain
  2. nitroglycerin, a NO donor well known for its vasodilator and antihypertensive action, induces penile erection and yawning when administered centrally or in the PVN. Despite these findings, which support a key role of paraventricular NO in the control of penile erection and yawning, and the fact that the PVN receives a dense serotoninergic projection from the medullary raphe nuclei, the inability of NAME when injected directly into the PVN to prevent in-CPP-or TFMPP-induced penile erection yawning suggests that paraventricular NO is not involved in the 5-HT1c receptor agonist-induced responses.
The finding also rules out the possibility that m-CPP or TFMPP induces penile erection and yawning by activating oxytocinergic transmission, possibly by increasing NO synthase activily in paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas.
This is in agreement with previous findings showing thal m-CPP and TFMPP injected in the PVN falled to induce penile erecction and yawning, and that their effect was not prevented by a potent oxytocin antagonist given i.c.v., unlike apomorphine. NMDA, nitroglycerin and oxytocin itself. Il is then more likely that 5-HT1c receptor agonists induce and NO-synthase inhibitors prevent these responses by acting at sites located downstream of processes involving oxytocin in some yet unidentified brain area. In this regard, it is pertinent to recall thal a serotoninergic pathway originating in the nucleus paragigantocelluris of the ventral medullaa sending projections to the lumbar spinal cord in the region of the spinal nucleus of the bulbo cavernuosus inhibits penile erection has been recently identifie. Perhaps more intriguing, NO-synthase was recently localized in neurons of the ventral medulla, including the nucleus paragigantocellularis as well as of the spinal cord. Since electolytic lesions of the nucleus paragigantocellularis facilitate penile reflexes and copulatory behavior in male rats and drugs that enhance 5-HT transmission, especially 5HT2 receptor agonists, impair these sexual responses, it is tempting to speculate that NO-synthase inhibitors prevent m-CPP and TFMPP-induced penile erection by inhibiting NO synthase in the medulla and/or the spinal cord. This is in agreement with the possibility that penile erection by 5-HT1c receptor agonists is rnediated by the stimulalion of post-synaptic 5-HT1c receptors in the ventral medulla and/or spinal nucleus of the bulbocavernosus.

As to the molecular mechanisins by means of which NO, formed by 5-HT1c receptor stimulation, induces penile erection and yawning, one possibility is that m-CPP and TFMPP activate the so-called NO-cyclicguanosine 3': 5' monophosphate (cGMP) pathway. In agreement with this hypotliesis m-CPP- and TFMPP-induced penile erection and yawning are prevenied by inhibitors of guanylate cyclase, a major target of NO, such as methyleneblue and LY 83583. Since NO-synthase containing neurons are often just opposed to guanylate cyclase-containing largels, the stimulation of 5-HT1c receptors would lead to the activation of NO synthase, thereby producing NO which would in turn act as an intercellular messager activating guanylate cyclase in target cells mediating penile erection and yawning. However, this interpretation is complicated by the inability of the potent NO scavenger hemoglobin to preventm-CPP or TFMPP responses. In fact, this high molecular weight substance would bind NO exclusively in the extraccellular space, being unable to cross cellular membranes, precluding it from reacaching larget cells, thereby preventing, the activation of guanylate cyclase and in turn the behavioral responses. One unilving explanation for such discrepancy might be that NO acts as an intracellular messenger activating, in turn those neuronsni which is formed, thereby releasing a neurotransmitter(s) that activates a methylene blue- or LY 83583-sensitive guanylate cyclase in areas involved in the control of these bahavioral responses. If the latter hypothesis were correct, NO would act on a larget different from guanylate cyclase, that is by a c-GMP- independent mechanism. Indeed, NO might interact with numerous other enzymes that, like guanylate cyclase, bind metal ions such as iron, as described for instance in fibroblasts. Accordingly, NO donors were found to be able to activate the ADP-ribosylation, catalyzed by cellular ADP-ribosyl-transferases, of several brain proteins including glyceraldehyde-3'-phosphate dehydrogenase and guanosine triphosphate (GTP) binding proteins. In addition to the points discussed above, other arguments against a direct activation by NO of guanylate cyclase after m-CPP or TFMPP come from the possibility of methylene blue to inhibit directly NO-synthase and of LY 83583 Io inhibit indirectly guanylate cyclase, for instance by generating superoxide anion radicals that act as NO scavengers.

Although further studies are necessary to identify the brain site(s) where NO-synthase inhibitors act to prevent m-CPP- and TFMPP-induced penile erection and yawning and to clarify the role of guanylate cyclase, the present results provide further evidence for a key role of central NO in the control of these behavioral responses.

Involvement of 5-HT1c-receptors in drug-induced penile erections in rats H Berendsen

Influence of sildenafil on central dopamine-mediated behaviour in male rats F Ferrari