mise à jour du
11 mars 2004
Phamcol Biochem Behav
1994; 48; 3; 799-804
Prevention by n g -nitro-l-arginine methyl ester of apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain
MR Melis, R Stancampiano, A Argiolas
Bernard B. Brodie Department of Neuroscience, University of Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Penile erection and yawning are two different behavioral patterns that often occur concomitantly in physiological and experimental conditions. Oxytocin and apomorphine are among the most potent substances able to induce penile erection and yawning discovered so far and a neuronal dopamine-oxytocin link in the paraventricular nucleus of the hypothalamus (PVN) seems to be involved in the induction of these behavioral responses. As far as the molecular mechanism by means of which apomorphine and oxytocin induce these behavioral effects is concerned, calcium and pertussis toxin-sensitive G proteins seem to be involved, because nanograrn amounts of the potent N-type calcium channel blocker omega-conotoxin-GVIA or of pertussis toxin prevent the above symptomatology when injected in the PVN.
Recently we found that both peripheral and central administration of inhibitors of nitric oxide (NO) synthase, the enzyme responsible for the formation of NO, prevent apomorphine- and oxytocin-induced penile erection and yawning, suggesting that this novel discovered transduction messenger is also involved in the control of these responses induced by apomorphine and oxytocin. To further characterize the role of NO in the control of these responses, we studied the effect of the microinjection of Ng-nitro-L-arginine methyl ester (NAME), one of the most potent inhibitors of NO synthase available so far, in different brain areas on apomorphine- and oxytocin-induced penile erection and yawning. Moreover, because NO is supposed to act by stimulating guanylate cyclase to produce cyclic guanosine 3',5' monophosphate (cGMP), the effect of the central microinjection of methylene blue, an inhibitor of guanylate cyclase on apomorphine and oxytocin-induced penile erection and yawning was also studied. [...]
Discussion : The present resuits show that the PVN is a brain site where NO synthase inhibitors act to antagonize penile erection and yawning induced by apomorphine or oxytocin. In agreement with this hypothesis, the PVN is one of the most rich brain areas containing NO synthase-immunostaining neurons. This confirms and extends previous results showing that central NO is involved in the control of these behavioral responses. In particular, the ability of NAME to prevent penile erection when injected in the PVN not only suggests that this novel neurotransmitter is involved in the control of this primary sexual function, but also, provides further evidence for a major role of this hypothalamic nucleus in the control of sexual functions strictly related to the consummatory phase of sexual behavior, ie., penile erection, penile reflexes, and seminal emission.
The mechanism by which NAME acts in the PVN to prevent penile erection and yawning is unknown, and only some speculation is possible at present. If one assumes that apomorphine induces these responses by activating oxytocinergic neurons in the PVN (see introductory paragraphs), NAME might act by preventing the activation of oxytocinergic transmission.
In this respect, it is pertinent to recall that apomorphine and oxytocin effects seem to be mediated by an increase in calcium ion influx. As already suggested for the NMDA receptorcoupled calcium channel, calcium ions might bind to calmodulin activating in turn NO synthase to produce NO that activates guanylate cyclase to increase cGMP production. If this hypothesis were correct, NO would be considered either as a second messenger, like calcium ions, or a neurotransmitter itself that mediates penile erection and yawning induced by apomorphine and oxytocin. In agreement with the above hypothesis, oxytocinergic neurons, when activated by apomorphine or oxytocin itself (see, should produce NO that might be released cither by neuronal cell bodies and/or nerve endings to act as a neurotransmitter activating in turn the production of cGMP in target cells or might act intracellularly as a second messenger.
A neurotransmitter role of NO at sites distant from the PVN is favored by the results obtained with methylene blue, an inhibitor of guanylate cyclase in several tissues, ie., platelets and vascular smooth muscles. Indeed, methylene blue is unable to prevent penile erection and yawning induced by apomorphine and oxytocin when injected in the PVN, but is fully active when injected ICV. This implies that cGMP is involved in the effects of apomorphine and oxytocin in some yet undiscovered brain area. This explanation should be considered with caution, because it was recently reported that methylene blue can inhibit directly NO synthase rather than guanylate cyclase. However, the inability of methylene blue, unlike NAME, to prevent penile erection and yawning when injected in the PVN does not support such possibility in our experimental conditions.
On the other hand, the ineffectiveness of methylene blue injected in the PVN might indicate that NO released by oxytocinergic cell bodies in the PVN influences the expression of penile erection and yawning by acting with a mechanism not related to the activation of guanylate cyclase, that is, by a cGMP-independent mechanisin. NO infact might interact with numerous other enzymes that, like guanylate cyclase, bind metal ions such as iron, as described for instance in fibroblasts. The identification of the brain area in which the inhibition of guanylate cyclase by methylene blue or other inhibitors prevents apomorphine and oxytocin responses will clarify this point.
The above interpretations are in line with the existence of a neuronal dopamine-oxytocin link that controls these behavioral responses, in particular, with previous findings showing that apomorphine effect on penile erection and yawning are prevented by oxytocin antagonists given ICV but not injected into the PVN. However, the prescrit results do not rule out the possibility that NAME induces its effects by acting in the PVN at targets different from the cell bodies of parvocellular oxytocinergic neurons that send their projections to several brain areas. Indeed, to our knowledge, it is unknown whether these oxytocinergic neurons contain NO synthase or not, although the coexistence of the enzyme with vasopressin in magnocellular neurons has been recently reported.
In conclusion, the present results suggest that NO via a cGMP-depenilent mechanism is involved in the control of penile erection and yawning induced by apomorphine or oxytocin.