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du 16 janvier 2003
Pharmacol Biochem Behav 1992;42(1):61-66
 cas cliniques
A hippocampal oxytocin mediates apomorphine-induced penile erection and yawning
Melis MR, Stancampiano R, Argiolas
 
Department of Neuroscience, University of Cagliari
 
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

Chat-logomini

Penile erection and yawning are two different behavioral patterns that often occur concomitantly under physiological and experimental conditions. While the importance of penile erection in reproduction of mammals does not need to be stressed, it is pertinent to recall that yawning, alone or associated with stretching, is considered an ancestral vestige surviving throughout evolution that subserves the purpose of arousal.
 
Several lines of experimental evidence suggest that a central dopamine-oxytocin link plays a key role in the expression of such symptomatology. Accordingly, both apomorphine and oxytocin induce penile erection and yawning when unilaterally injected in the paraventricular nucleus (PVN) of the hypothalamus; lesions of the PVN abolish apomorphine and oxytocin responses; dopamine receptor blockers prevent apomorphine but not oxytocin effects; nonapeptide oxytocin antagonists prevent apomorphineinduced penile erection and yawning; finally, apomorphine increases oxytocin content in brain, as well as in plasma.
 
The above results support the hypothesis that apomorphine and dopaminergic agonists induce penile erection and yawning by releasing oxytocin in the CNS by acting in the PVN. In this regard, it is pertinent to recall that the PVN contains not only the majority of the cell bodies of those oxytocinergic neurons, which project to extrahypothalamic brain areas, that is, septum, hippocampus, olfactory bulb, brain stem, pons, medulla and spinal cord, but also dopaminergic neurons, located in the proximity of oxytocinergic cell bodies, that belong to the incertohypothalamic dopaminergic system.
 
Recently, it has been shown that septohippocampal lesions prevent apomorphine-induced penile erection and yawning. Taken together with the finding showing that oxytocin induces penile erection and yawning when bilaterally injected into the CA1 field of the hippocampus, this raises the possibility that the oxytocinergic pathways activated by apomorphine and that mediate penile erection and yawning are those projecting to the septum and hippocampus.To verify such a hypothesis, we studied:
  1. the effect of a potent oxytocin nonapeptide antagonist injected into the PVN on apomorphine- and oxytocin-induced penile erection and yawning;
  2. the effect of oxytocin and apomorphine microinjected in the medial septum (NIS) on these behavioral responses;
  3. the effect of electrolytic lesions of the MS on oxytocin-induced penile erection and yawning, as well as on oxytocin concentration in the hippocampus.
The present study shows that the oxytocin antagonist Orn-vasotocin injected in the PVN prevents penile erection and yawning induced by oxytocin but not by apomorphine, while MS lesions that decrease hippocampal oxytocin concentration prevent the above behavioral responses induced by apomorphine but not oxytocin. These results extend previous findings suggesting that the dopaminergic agonist apomorphine induces penile erection and yawning by releasing oxytocin in the CNS.
 
In particular, the failure of d(CH2),Tyr(Me)-Orn8-vasotocin to prevent apomorphine response when injected in the PVN, in spite of its efficacy when given ICV, suggests that apomorphine induces penile erection and yawning by increasing oxytocinergic activity by acting directly on dopaminergic receptors at the level of the oxytocinergic cell bodies or indirectly by removing some inhibitory input on oxytocinergic neurons, rather than by releasing oxytocin in the PVN. On the other hand, the ability of d(CH2)5Tyr(Me)-Orn8-vasotocin injected into the PVN to prevent ICV or PVN oxytocin response confirms that oxytocin acts mainly in the PVN to induce penile erection and yawning possibly by stimulating specific oxytocinergic receptors located in this hypothalamic nucleus.
 
In line with the hypothesis that apomorphine induces penile erection and yawning by activating oxytocinergic neurons, it is likely that oxytocin also induces the above responses by increasing its own transmission, perhaps by stimulating oxytocinergic receptors located in the cell bodies of its own neurons in the PVN. Accordingly, exogenous oxytocin injected in the PVN has been found capable of activating its own release in vivo and in vitro from magnocellular neurons, and immunoreactive oxytocinergic synapses have been found to impinge on the cell bodies of oxytocinergic neurons in both hypothalamic supraoptic and paraventricular nuclei.

In agreement with the above hypotheses, the failure of apomorphine to induce penile erection and yawning when injected directly in the MS or in the hippocampus or in MS-lesioned rats, although effective when injected in the PVN, suggests that apomorphine induces the above responses by activating those oxytocinergic pathways originating in the PVN that reach the medial septum or the rostral hippocampus (tenia tectae) passing rostrally to the septum. The second possibility is the most likely, being favored by the failure of oxytocin to induce penile erection and yawning when injected in the MS, by the finding showing that MS lesions decrease hippocampal oxytocin concentration only in those animals found unresponsive to apomorphine and by the failure of iontophoretically applied oxytocin to activate MS neurons.

The ineffectiveness of apomorphine to induce penile erection and yawning when injected into the MS is in contrast with previous studies showing that the bilateral injection of apomorphine into the lateral septum induces yawning. The discrepancy might be explained by the fact that in those studies doses of apomorphine (10 jug and higher per site) were used that were too high and probably resulted in the spread of the drug to the active site. Accordingly, it is unlikely that apomorphine acts directly in the MS, although a septohippocampal dopamine-acetylcholine link has been supposed to be involved in the expression of yawning and pende erection. In fact, if the latter hypothesis were correct, the stimulation of dopaminergic receptors in the MS would induce a cholinergic inhibition mediating in turn pende erection and yawning. Against such hypothesis, muscarinic agonists induce the above behavioral responses, possibly acting in the hippocampus, and blockade of cholinergic transmission by muscarinic antagonists atropine and scopolamine, as well as by MS lesions, which decrease hippocampal acetylcholine content, prevent apomorphine response.

Taken together with the inability of MS lesion to prevent oxytocin response, the above results suggest that apomorphine induces penile erection and yawning by activating selectively the hypothalamic-hippocampal oxytocinergic projection. In this respect, it is noteworthy that the hippocampus plays a key role in the expression of penile erection and sexual behavior, apomorphine increases oxytocin content in this brain area at doses that induce penile erection and yawning, oxytocin induces these behavioral responses when injected in the CA1 field of the hippocampus, and oxytocin excites hippocampal neurons by acting on uterine-type oxytocinergic receptors, those that mediate penile erection and yawning. Nevertheless, it is likely that this hypothalamic-hippocampal oxytocinergic pathway plays only a minor role or is not involved at all in the oxytocin response. In fact, the inability of MS lesion to prevent the effect of oxytocin injected in the PVN raises the possibility that oxytocin may act in the PVN to induce penile erection and yawning by stimulating other neuronal pathways not involving the hippocampus, that is, the oxytocinergic projections reaching the pons, medulla, and spinal cord. Accordingly, the PVN is considered a sort of integration center between the central and autonomic nervous systems. In view of the prevention of oxytocin effect by PVN lesions but not by MS lesions, it is tempting to speculate that a hippocampal-hypothalamic pathway, whose activity is modified by apomorphine treatment, mediates in turn the activity of the same neuronal circuits modified by PVN oxytocin and controlling the above behavioral responses. In agreement with this hypothesis, neuronal pathways originating in the hippocampus and septum that exert an excitatory input on vasopressinergic and oxytocinergic neurons in the PVN have been described.

The involvement of oxytocin in different central neuronal pathways that control penile erection and yawning deserves some comment.

 
One of these pathways, that is, the hypothalamic-hippocampal oxytocinergic pathway, is activated by apomorphine and probably by other dopaminergic agonists through the stimulation of D, dopamine receptors in the PVN. Interestingly, the PVN contains the A14 group of the so-called incertohypothalamic dopaminergic system. These small dopaminergic neurons arborize extensively and surround the oxytocinergic neuronal cell bodies in the PVN. This suggests that this still poorly characterized hypothalamic dopaminergic system plays a major role in the expression of yawning and penile erection.
 
Since the hypothalamus, the first developed brain structure from a phylogenetic point of view, plays a primary role survived during evolution from fishes to primates in reproduction, it is easy to speculate that hypothalamic oxytocin is involved in the control of penile erection in mammals. The involvement of oxytocin in the expression of penile erection in brain areas phylogenctically developed later, but strictly connected to the hypothalamus (ie., the limbic system), might be one of those mechanisms by means of which high brain centers control such a primary sexual function. In particular, the activation of central oxytocinergic pathways by dopamine, a neurotransmitter involved in motivation and rewarding mechanisms, raises the possibility that oxytocin in the limbic system plays a role in sexual arousal and motivation (libido in men), while its action in the hypothalamus may be related mainly to erectile and ejaculatory performance (potency in men).