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mise à jour du
11 mars 2004
Regulatory Peptides
1997;69:105-11
Oxytocin increases nitric oxide production
in the paraventricular nucleus of the hypothalamus
of male rats: correlation with
penile erection and yawning
MR Melis, S Succu, U Iannucci, A Argiolas
 
Bernard B. Brodie Department ofNeuroscience, Cagliari, Italy

Chat-logomini

Introduction
Penile erection and yawning are two different behavioral patterns that often occur concomitantly in physiological and experimental conditions. While the importance of penile erection in reproduction does not need to be stressed, yawning alone or associated with stretching can be considered an ancestral vestige surviving through evolution that subserves the purpose of arousal. Among substances that induce both behavioral responses, the neurohypophyseal peptide, oxytocin, centrally administered, is certainly one of the most potent. This effect is mediated by the stimulation of specific uterinetype oxytocinergic receptors, possibly located in the paraventricular nucleus of the hypothalamus (PVN) being induced by oxytocin-related peptides and prevented by selective oxytocin receptor antagonists, given centrally with a potency that was parallel with the potency of these compounds in stimulating and blocking oxytocinergic receptors, respectively. These oxytocin responses are apparently mediated by the stimulation of oxytocinergic neurons originating in the PVN and projecting to extrahypothalamic brain areas. These neurons seem to mediate penile erection and yawning induced not only by oxytocin but also by dopamine receptor agonists and N-methyl-D-aspartic acid.
 
We recently found that oxytocin, apomorphine, Nmethyl-D-aspartic acid, but not serotonin, receptor agonists, induce penile erection and yawning by activating NO synthase in the PVN, which in turn leads to the activation
of central oxytocinergic transmission. This suggests that the recently discovered neurotransmitter/neuromodulator, nitric oxide (NO) is involved in the control of penile erection and yawning induced by these substances. In agreement with this hypothesis, NO synthase has been identified in the cell bodies of paraventricular oxytocinergic neurons and NO donors injected into the PVN induce penile erection and yawning indistinguishable from those induced by apomorphine, oxytocin, N-methyl-D-aspartic acid which, however, are prevented by the oxytocin receptor antagonist d(CH,-)5Tyr(Me)-Orns-vasotocin injected into the lateral ventricles (i.c.v.). In order to provide further support for a role of paraventricular NO in penile erection and yawning induced by oxytocin, we studied the effect of a dose of oxytocin and related peptides that induce penile erection and yawning on the concentration of the reaction products of newly formed NO with O2, NO2 and NO in the dialysate collected from a vertical microdialysis probe implanted in the PVN of male rats. Indeed, the concentration of NO, and NO- in the dialysate represents an indirect but reliable indicator of NO production in vivo. [...]
 
Discussion
The present results show that a dose of oxytocin that induces penile erection and yawning increased basal NO, and, but to a lesser extent, NO concentration in the PVN dialysate of male rats. NO2 concentration was also increased by the oxytocin-related peptides [Thr 4 Gly'loxytocin and oxytocin(1-8) that, like oxytocin, induce penile erection and yawning, but not by oxytocin(I-6) and oxytocin(7-9), which were unable to induce these behavioral responses. These findings are in line with the hypothesis that oxytocin induces penile erection and yawning by activating its own receptors in the PVN and that the stimulation of these receptors leads to the activation of paraventricular NO synthase. Accordingly, d(CH2)5Tyr(Me)-Orn8-vasotocin, a selective oxytocin receptor antagonist, prevented not only penile erection and yawning but also the NO2 concentration increase induced by oxytocin in the PVN dialysate. As to the mechanism by means of which oxytocin activates NO synthase in the PVN, one posisibility is that oxytocin increases Ca2+ influx in the cell bodies of oxytocinergic neurons mediating penile erection and yawning, since these neurons contain NO synthase, which is Ca2+ calmodulin-dependent, and Ca2+ ions mediate the oxytocin effect on penile erection and yawning.
 
Furthermore, the increase of NO2 and NO3 concentration in the PVN dialysate induced by oxytocin and related peptides found in this study, like that induced by dopamine agonists, which induce penile erection and yawning by increasing oxytocinergic transmission, would reflect almost exclusively an increased conversion of L-arginine to NO that is, in turn, oxidized mainly to NO2 and, te, a lesser extent, to NO3 , as found in other biological fluids not containing blood cells. In agreement with the above hypothesis, this study shows that L-NAME, a potent inhibitor of NO synthase given i.c.v., prevented oxytocin-induced increase of NO, concentration, penile erection and yawning. Conversely, the oxytocin-induced increase of NO2 concentration was also prevented by hemoglobin, a potent NO scavenger.
 
However, the hypothesis that an increase of NO production by NO synthase is correlated to an increase of these behavioral responses is complicated by the inability of hemoglobin to prevent oxytocin-induced penile erection and yawning, despite its ability to prevent the increase of NO, concentration in the PVN. Nevertheless, NO, is measured in the extracellular dialysate, while NO is formed by NO synthase intracellularly. A possible explanation for this contradiction is that NO formed by oxytocin stimulation of oxytocinergic receptors in the PVN acts as an intracellular messenger, rather than an extracellular transmitter, in those neurons, inducing these behavioral responses. In fact hemoglobin would be expected to scavenge only extracellular and not intracellular NO, because it is unable to cross cellular membranes because of its high molecular weight. However, this does not rule out the possibility that NO released from those cells by which it is produced, acts as an extracellular transmitter and is involved, for instance, in other hypothalamic effects of oxytocin.
 
The present results show also that the dopamine receptor antagonist, haloperidol, is unable to prevent oxytocin effects on NO2 concentration, penile erection and yawning, despite its ability to prevent these responses when induced by dopamine agonists. This is in agreement with previous studies showing that dopamine acts before oxytocin in the PVN for the induction of these behavioral responses. In fact, if one assumes that dopamine agonists and oxytocin increase PVN NO synthase in the same oxytocinergic neurons mediating penile erection and yawning, by stimulating specific dopaminergic and oxytocinergic receptors, respectively, haloperidol would prevent dopamine agonist- but not oxytocininduced responses.
 
As to the mechanism by means of which NO produced in the PVN by oxytocin leads to the activation of oxytocinergic neurons mediating penile erection and yawnîng, the inability of methylene blue, an inhibitor of guanylate cyclase one of the best known targets of NO in preventing the increase of NO2 concentration induced by oxytocin as well as penile erection and yawning when injected in the PVN provides further support to the hypothesis that NO acts in the PVN to control these behavioral responses by a mechanism not related to the activation of guanylate cyclase. Accordingly, the injection of a stable cyclic guanosine 3':5'-mono-phosphate analog (e.g., 8-bromo-cyclic guanosine 3': 5'- mono- phosphate) in the PVN, unlike that of nitric oxide donors, was found to be unable to induce penile erection and yawning. Nevertheless, since methylene blue given i,c.v. prevents these behavioral responses induced by oxytocin, the possibility that guanylate cyclase is involved in the control of penile erection and yawning in sites distant from the PVN cannot be ruled out.
 
In conclusion, the present results suggest that oxytocin and oxytocin-related peptides at doses that induce penile erection and yawning, increase the concentration of NO2 and NO3 in the PVN dialysate. Since NO2 and NO3 concentration in extracellular fluids is a reliable index of the activity of NO synthase, these results provide further evidence that NO plays an important role in the control of these behavioral responses ut the level of this hypothalamic nucleus.