mise à jour du
1 septembre 2003
Brain Research Bulletin
1993; 32; 71-74
Nitric oxide synthase inhibitors prevent apomorphine- and oxytocin-induced penile erection and yawning in male rats
 Maria Rosaria Melis, Salvatora Succu and Antonio Argiolas
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Penile erection and yawning are two différent behavioral patterns that often occur concomitantly in physiological and experimental conditions. Studies from our and other laboratories have shown that dopaminergic agonists, such as apomorphine and oxytocin, are among the most potent inducers of such a symptomatology in male rats, and a neuronal dopamine-oxylocin link occuring in the paraventricular nucleus of the hypothalamus (PVN), is supposed to have key role in the expression of these behavioral patterns. As far as the molecular mechanisms activated by dopaminergic agonists and oxytocin in the paraventricular nucleus are concerned, calcium and pertussis toxin-sensitive G proteins seem to be involved in the expression of these behavioral patterns, because nanogram amounts of the potent N-type calcium channel blocker omega-conotoxin-GVIA or pertussis toxin prevents the above symptomatology when injected in the hypothalamic nucleus.
We show here that the peripheral and central administration of N-nitro-L-arginine methyl ester (NAME) and N'-monomethyl-L-arginine (NNINIA), inhibitors of nitric oxide (NO) synthase, the enzyme responsible for the formation of NO, a novel discovered transduction messenger in the peripheral and central nervous system, prevents apomorphine- and oxytocin-induced penile erection and yawning. [...]

The present results show that the systemic as well as the central administration of NAME or NMMA, but not D-NMMA, prevent penile crection and yawning induced by apomorphine and oxytocin. The above effect seems to be caused by the inhibition of NO synthase, because the potency of these compounds in preventing penile erection and yawning is parallel to their potency in inhibiting the activity of this enzyme in brain. The ability of NO synthase inhibitors to prevent penile erection when given IV is in agreement with recent studies showing that NO is a physiological mediator of penile erection at the level of the penile vasculature. Accordingly, NAME and NMMA given IV were found to capable of preventing penile erections induced by the electrical stimulation of the cavernous nerve (NAME was about 6 times more potent than NMMA). Nevertheless, the ability of NAME and NMMA when given into one of the lateral ventricles to prevent penile erection and yawning induced by apomorphine and oxytocin suggests that central rather than peripheral NO synthase is involved in the control of these behavioral responses induced by apomorphine and oxytocin. In agreement with this hypothesis, both apomorphine and oxytocin act in the PVN to induce penile erection and yawning, and this nucleus bas been shown to contain NO synthasecontaining neurons. Although the neurotransmitters of these hypothalamic neurons have not been yet identified, the results suggest that oxytocin acts on neurons whose activity is dependent from a normal level of NO. Because NO stimulates soluble guanylate cyclase by binding with high affinity to iron in the heme of guanylyl cyclase, eliciting a conformational changes that enhances the catalytic activity of the enzyme, thus increasing the concentration of cyclic guanosine 3',5' monophosphate (cGMP) in several tissues such as macrophages, vascular smooth muscles, and brain, it is tempting to speculate that a decrease in the content of this second messenger which, in turn, activate protein phosphorilation by eGMP-dependent protein kinases, might be responsible for the inhibition of oxytocin responses by NO syntetase inhibitors. If the above hypotesis were correct, one would suggest that oxytocin is acting through the activation of a cGMP-dependent mechanism secondary to an increased calcium influx through the neuronal membranes of the target cells. In agreement with this hypothesis, oxytocin-induced penile erection and yawning are prevented by calcium channel blockers such as omega-conotoxin-GVIA. A similar model has been proposed to explain the blockade by NO synthase inhibitors of the increase in cGMP induced by glutamate or N-methyl-D-aspartate (NMDA) in cerebellar slices. In this preparation, stimulation of the ion channel-coupled NMDA glutamic acid receptor subtype induces a calcium ion influx. Calcium ions bind to calmodulin activating NO synthase to produce NO, thereby stimulating guanylate cyclase. Although the mechanism by means of which cGMP might mediate penile erection and yawning is unknown, the above interpretation can be applied also to explain the inhibition by NO synthase inhibitors of apomorphine-induced penile erection and yawning, if one assumes that apomorphine induces the above responses by stimulating oxytocinergic transmission in the PVN (see the Introduction section). However, the possibility that NO synthase inhibitors act before oxytocin in order Io inhibit apomorphine responses cannot be ruled out at present, and further studies are necessary to clarify this point.

In conclusion, our results suggest that NO plays a key role in the expression of yawning and a primary sexual function such as penile erection, not only in the periphery at the level of the penile vasculature, but aiso in the central nervous system.