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23 décembre 2004
1989; 97; 383-387
Oxytocin-induced penile erection and yawning in male rats: effect of neonatal monosodium glutamate and hypophysectomy
A. Argiolas, M.R. Melis, A. Mauri, G.L. Cessa
Department of Neurosciences, University of Cagliari, Italy
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Penile erection and yawning are two different behavioural patterns that often occur concomitantly under physiological and experimental conditions (see Holmgren et al. 1985). Penile erection is one of the most important sexual responses in mammals, including man, its achievement being essential for the success of reproduction. However, this sexual response can be observed not only during sexual interaction but also in other contexts, such as after simple manipulation of the genitalia or during sleep and erotic fantasies in humans. Depending on the particular context in which penile erection occurs, different neural and/or endocrine mechanisms may participate in its regulation. As to the physiological significance of yawning, it is pertinent to recall that yawning is considered to have a role in increasing attention when sleep is pressing in dangerous situations or social circumstances (for a review on the physiological significance of yawning see Bertolini and Gessa 1981).
Among the various agents able to induce both penile erection and yawning, oxytocin injected into a lateral ventricle (ICV) of the rat is certainly one of the most potent discovered so far (Argiolas et al. 1986). Oxytocin effects are thought to be mediated by a direct action of the peptide on the hypothalamic paraventricular nucleus (PVN). Accordingly, the PVN has been found to be the most sensitive brain area for the induction of these behavioural responses by oxytocin (Melis et al. 1986), and electrolytic lesions of this nucleus caused a marked decrease in the number of yawning and penile erection episodes induced by oxytocin (Argiolas et al. 1987b). In male rats yawning and penile erection can also be induced by the systemic administration of low doses of dopamine (DA) agonists (see Serra et al. 1983) and by the ICV injection of adrenocorticotropin (ACTH) and related peptides (see Bertolini and Gessa 1981). Recent experimental evidence from our laboratory suggested that 1) DA agonists induce yawning and penile erection by releasing oxytocin in the central nervous system, possibly in the PVN (Argiolas et al. 1987b, c; Melis et al. 1987); 2) DA agonists do not induce their effect by releasing an ACTH-derived peptide in the hypothalamus (Argiolas et al. 1987 a), and 3) the hypophysis is necessary for the induction of yawning and penile erection by DA agonists and ACTH-derived peptides (Serra et al. 1983, 1987). In order to verify if oxytocin induced the above behavioural responses by releasing an ACTH-derived peptide in the hypothalamus, and if the pituitary is necessary for the expression of yawning and penile erection induced by oxytocin, we have studied the effect of ICV injection of oxytocin on yawning and 'penile erection in hypophysectomized rats and in rats neonatally treated with monosodium glutamate (MSG), a treatment that induces almost complete depletion of ACTH-like peptides in the hypothalamus (Eskay et al. 1979; Krieger et al. 1979). (...)
The present results confirm and extend previous findings from our laboratory showing that ICV oxytocin induces penile erection and yawning with a bell-shaped U-inverted dose-response curve. The reason for such a dose-response curve is unknown at present, although similar dose-response curves have been reported for other behavioral effects of oxytocin (Bohus et al. 1978; Kovacs et al. 1985). A possible explanation for the ineffectiveness of high doses of oxytocin is that the peptide stimulates brain areas other than those responsible for the appearance of penile erection and yawning, which have an inhibitory effect on the above responses. In agreement with this hypothesis, no bellshaped dose-response curve was observed when increasing doses of oxytocin were injected into the PVN (Argiolas et al. 1988a).
Moreover, the present results show that hypophysectomy prevents the oxytocin effect. Although the prevention was not complete, suggesting that central mechanisms mediating penile erection and yawning are still operative, this finding is in line with previous observations showing that intact pituitary function is critical for the induction of the above behavioural responses by oxytocin and other agents as well. Indeed, hypophysectomy has been found to strongly reduce penile erection and yawning induced by either the DA-agonist apomorphine (see Serra et al. 1983) or ACTH 1-24 (Serra et al. 1987). Moreover, the testosterone reversal of the effect of hypophysectomy on penile erection suggests that this hormone, released from the testis by the pituitary luteinizing hormone (LH), also has a permissive role in the expression of this behavioural response. This is in agreement with previous findings showing that testosterone reverses the inhibitory effects of castration on sexual behaviour (for a review see Sachs and Meisel 1988), including the prevention of ACTH-induced penile erection (Bertolini and Gessa 1981). It is likely that the partial effect of testosterone reflects that hypophysectomy effects are more dramatic than those of castration, and that more complete replacement therapy with other pituitary and endocrine hormones in addition to testosterone might be much more effective in this case (see Eaves et al. 1985). On the other hand, the lack of effect of testosterone on yawning indicates that the mechanisms mediating penile erection and yawning can be dissociable, although common mechanisms may participate in their concomitant occurrence under certain physiological or experimental conditions (see Hoimgren et al. 1985). All together, the above findings suggest that the pituitary gland and its target tissues (gonads, adrenals, thyroid) have a permissive (perhaps even synergistic) role in the expression of the above behavioural responses induced by oxytocin, ACTH and apomorphine. The pituitary and pituitary-controlled glands might control the above responses directly (i.e., by means of pituitary or endocrine hormones which act directly on the central nervous system) or indirectly (i.e., by means of pituitary hormones which control the release of endocrine hormones by target tissues or by means of endocrine hormones which modulate the activity of pituitary hormones). The mechanism by which such control occurs is not known and only speculation is possible at present. One possibility is that pituitary and/or endocrine hormones influence the interaction of oxytocin and other pharmacological agents with their receptors and/or alter the response that usually follows the drugreceptor interaction.
In contrast, the depletion of ACTH-MSH-like peptides by neonatal MSG treatment was completely ineffective in modifying oxytocin-induced penile erection and yawning. Although it is possible that hypothalamic ACTH-MSH peptides remaining after MSG can still be released in amounts sufficient to mediate oxytocin effect by the surviving opiomelanotropinergic neurons, perhaps becoming superactive to overcome the lesion damage, this finding suggests that oxytocin does not induce the above responses by releasing an ACTH-MSH-like peptide in the hypothalamus. This is in agreement with previous findings from our laboratory showing that ACTH and derived peptides induce their effect by acting at sites located downstream to DA or oxytocin receptors or by a different mechanism, not involving DA or oxytocin. Indeed, unlike oxytocin- and apomorphine-induced response, ACTH-induced penile erection and yawning are not antagonized by the potent oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin (Argiolas et al. 1987c), nor by electrolytic lesion of the hypothalamic PVN (Argiolas et al. 1987b). Conversely, it is unlikely that oxytocin induces the above responses by releasing an ACTH-derived peptide in extrahypothalamic brain areas not affected by MSG treatment, since the hypothalamus was found to be the most sensitive brain area for the induction of yawning and penile erection by ACTH (Bertolini and Gessa 1981).
As to the relationship between oxytocin-induced penile erection and the physiology of penile erection and sexual behavior, the copulatory movements often followed by ejaculation induced by oxytocin suggest that the peptide activates neuronal pathways controlling the spinal cord which in turn regulates these penile and pelvic actions (for a review on this subject see Sachs and Meisel 1988). Accordingly, electrolytic lesion of the PVN caused almost complete depletion of oxytocin in brain and spinal cord (Lang et al. 1983), and abolished penile erection induced by oxytocin (Argiolas et al. 1987b). While our findings suggest that brain oxytocin is implied in the control of penile erection, other experimental evidence suggests that this effect of oxytocin may also occur in the regulation of sexual behavior. Accordingly, the ICV injection of a potent oxytocin antagonist, d(CH2)5Tyr(Me)-Orn8-vasotocin, inhibits male copulatory behavior in rats (Argiolas et al. 1988 b). In particular, this oxytocin analog influences all the parameters of copulatory behavior, the intromission and ejaculation latencies and the mount, intromission and ejaculation frequencies as well. In view of the ability of the oxytocin antagonist to prevent penile erection induced by oxytocin (Argiolas et al. 1987e), it is likely that the blockade of central oxytocm receptors induces an inability of the animals to achieve penile erection, which in turn causes a decrease in the intromission frequency and the abolition of ejaculation. The above findings correlate well with previous findings showing that 1) circulating levels of oxytocin are increased immediately after ejaculation in rabbits (Stoneham et al. 1985) and in the human sexual response (Carmichael et al. 1987), 2) ICV oxytocin has been found to increase lordosis behavior in female rats (Arletti and Bertolini 1985), and 3) oxytocm improves sexual performance of vigorous sexually experienced male rats in the presence of a female in oestrus, as indicated by the decrease in the post-ejaculatory interval observed in oxytocin-treated rats (Arletti et al. 1985). However, other studies have reported that oxytocin increases the post-ejaculatory interval, suggesting a specific role of the peptide in the control of this parameter of the copulatory behavior (Stoneham et al. 1985). This discrepancy might be due to the different doses of oxytocin used in the above studies (1 ng versus doses higher than 60 ng). More complete dose-response curves might clarify this point and perhaps reveal that oxytocin has a dual effect on the post-ejaculatory interval.
In conclusion, oxytocin apparently does not induce penile erection and yawning by releasing an ACTH-related peptide from opiomelanotropinergic neurons. Moreover, as for DA agonists and ACTH-derived peptides, intact pituitary function is necessary for the expression of these oxytocin induced behavioral responses.