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mise à jour du
27 mai 2004
Pharmacol Biochem Behav
Oxytocin-induced penile erection and yawning:
role of calcium and prostaglandins
Argiolas A, Melis MR, Stancampiano R, Gessa L
BB Brodie Department of Neurosciences, University of Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


The central administration of nanogram amounts of oxytocin induces repeated episodes of penile erection and yawning in male rats ). This effect seems to be mediated by the stimulation of specific uterine-type oxytocinergic receptors, being induced by oxytocin analogs with a potency that follows their oxytocic potency and prevented by nonapeptide antagonists with a rank order of potency that follows their antioxytocic activity. These receptors are probably located in the paraventricular nucleus of the hypothalamus (PVN), since microinjection studies have reveaIed this nucleus to be the most sensitive brain area for the induction of the above behavioral responses by oxytocin, while its destruction causes an almost complete prevention of oxytocin effect.
The involvement of uterine-type oxytocinergic receptors in the expression of oxytocin-induced penile erection and yawning raises the possibility that oxytocin is acting in the central nervous system to induce the above responses by a mechanism similar to that responsible for the induction of uterine contraction. In the uterus oxytocin receptor stimulation induces both calcium mobilization and synthesis of prostaglandins, other potent stimulants of the uterus which probably act synergistically with oxytocin during parturition. In order to verify whether or not calcium and prostaglandins play a role in the expression of oxytocin-induced penile erection and yawning, we have studied the effect of inhibitors of calcium channels and of prostaglandin synthesis on oxytocin-induced penile crection and yawning and the effect of microinjection of calcium and prostaglandins in the PVN on spontaneous penile erection and yawning as well. [...]
The present results show that organic calcium channel inhibitors prevent in a dose-dependent manner penile erection and yawning induced by oxytocin. Such effect of calcium channel inhibitors seems to be central, since it is observed not only after IP administration of the drugs, but also after their ICV injection. The finding suggests that oxytocin exerts its effect on penile erection and yawning by increasing calcium influx in some neuronal population of the rat brain. Indeed, verapamil, flunarizine, nifedipine, nimodipine and nicardipine are thought to be rather selective calcium channel inhibitors, although they belong to different chemical classes and differentially affect calcium channel subtypes.
The prevention of penile erection and yawning is observed at relatively high doses of calcium channel inhibitors. The requirement of such high doses probably reflects the presence of a subtype of calcium channel in the central nervous system different from that found in cardiac and smooth muscle tissue, which makes the nervous tissue poorly sensitive to the action of these compounds. The slightly higher potency of nimodipine and nicardipine might also be due to the greater affinity of these dihydropyridines for the nervous tissue than that of the other dihydropyridine nifedipine, the phenylalkylarnines (ie., verapamil) or the diphenylpiperazines (i.e., flunarizine). Accordingly, autoradiographic studies revealed high density of binding sites for nitrendipine in brain synaptosomes, which are not labeled by verapamil or diltiazem.
However, the possibility that the prevention of penile erection and yawning is due to unspecific effects of calcium channel inhibitors cannot be completely ruled out from the present results. At high doses, in fact, these compounds have been found able to inhibit not only calcium channels, but also sodium and potassium channels and to interact, at least in vitro, with central and peripheral a2-adrenergic and muscarinic receptors. However, it is unlikely that the prevention of oxytocin effect is due to adrenergic or muscarinic receptor blockade since alpha2-adrenergic antagonists have a facilitatory role on sexual activity and the interaction with muscarinic receptors is seen only at very high doses.
Despite the above possibility, further support for a role of calcium in the expression of penile erection and yawning induced by oxytocin is provided by the finding that elevation of calcium concentration in the PVN region, the most sensitive brain area for the induction of the above responses by oxytocin induces a similar symptomatology. In contrast, inhibition of prostaglandin synthesis by indomethacin or by aspirin was unable to alter oxytocin-induced penile erection and yawning, suggesting that prostaglandins are not involved in the expression of these behavioral responses. Accordingly, microinjection of prostaglandins in the PVN, unlike oxytocin or calcium gluconate, was unable to induce penile erection and yawning.
Taken together, the ability of calcium channel inhibitors to prevent oxytocin-induced penile erection and yawning and of calcium microinjections in the PVN to induce an oxytocin-like effect suggest that oxytocin induces the above behavioral responses by acting in the PVN by a mechanism similar to that operating in the uterus or mammary gland. Accordingly, oxytocin action on these peripheral tissues is dependent on the presence of intra- and extracellular calcium, but not of cyclic adenosinemonophosphate (c-AMP), and calcium channel inhibitors prevent oxytocin-induced uterine contractions This correlates well with our recent findings showing that uterine-type oxytocin receptors are involved in the induction of penile erection and yawning by oxytocin. Indeed, the structure activity relationship of oxytocin and related peptides for the induction of the above behavioral responses was found to be similar to that reported for the induction of uterine contraction or milk ejection.
As to the mechanism by which oxytocin mobilizes calcium to induce the above responses, only some speculation is possible at present. One possibility is that oxytocin activates directly calcium channels or influences one of the various biochemical systeins known to modify calcium homeostasis, such as phosphoinositide turnover, ATPase activity or calcium binding to calmodulin-like proteins. Some of these mechanisms have been reported to be operative in the uterus, but have not been yet demonstrated in brain. In particular, the data available so far in the literature suggest that oxytocin, unlike vasopressin, is unable to alter phosphoinositide breakdown in brain tissue even at relatively high doses. In spite of the lack of biochemical correlates, electrophysiological studies have shown that oxytocin is able to activate several neuronal populations in different rat brain areas including the hypothalannic supraoptic nucleus and PVN, the hippocampus and the dorsal motor nucleus of the vagus nerve. Interestingly, in the PVN, where oxytocin seems to act to induce penile erection and yawning, oxytocin excites its own neurons and this effect is strongly reduced in presence of low calcium/high magnesium media, suggesting the involvement of calcium influx in the above responses.
In addition to oxytocin, other substances induce repeated episodes of penile erection and yawning in rats. Among them are dopaminornimetic drugs, such as apomorphine. Recently, we have provided experimental evidence showing that this dopaminergic agonist induces these behavioral responses by releasing oxytocin in the central nervous system. Accordingly, apomorphine-induced penile erection and yawning are prevented by oxytocin receptor antagonists with a rank order of potency that follows their antioxytocic potency; the brain area most sensitive for the induction of the above effects either by oxytocin or apomorphine is the PVN; destruction of oxytocinergic neurons within the brain and spinal cord by electrolytic lesion of the PVN abolishes apomorphine-induced responses. If the above hypothesis were correct, apomorphine-induced response would be antagonized in a dose-dependent manner by calcium channel inhibitors, as found for oxytocin effect. Accordingly, we have found that calcium channel inhibitors prevent apomorphineinduced penile erection and yawning.
In conclusion, although further studies are necessary to clarify the mechanism responsible for calcium mobilization, the present data suggest that calcium is the second messenger which mediates oxytocin-induced penile erection and yawning.