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22 avril 2004
Pharmacol Biochem Behav 1987; 26; 503-507

Monosodium glutamate does not alter ACTH- or apomorphine-induced penile erection and yawning
A Argiolas, MR Melis, W Fratta, A Mauri, GL Gessa
Institute of Pharmacology, University of Cagliari, Italy

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The intracerebroventricular (ICV) injection of adrenocorticotropin (ACTH), alpha-melanocyte stimulating hormone (aMSH) and derived peptides, induces excessive grooming, yawning, stretching and penile erection in rats. While grooming occurs already at doses of 0. 1 nmol of ACTH or a-MSH, doses higher than 1-2 nmol are needed for inducing the latter effects. While the importance of penile erection in reproduction does not need to be further stressed, the other behaviours are important as indicators of arousal. In particular, grooming is believed to have a deactivating role in restoring behavioural homeostasis, while yawning, and stretching are believed to have the role of increasing attention when sleep is pressing in front of a danger or social circumstances. The above behavioural responses are thought to be mediated by a direct action of ACTH-MSH peptides in the hypothalamus, since this brain area has been found the most sensitive for the induction of the above effects by ACTH 1-24. Accordingly, recent studies have demonstrated the existence of neurons in the central nervous system containing proopiomelanocortin, the 31 kD protein precursor of ACTH, a-MSH and beta-endorphin. These neurons originate in the arcuate nucleus of the hypothalamus and send their projections to this and other brain regions.
 
Yawning and penile erection can be induced in rats also by the systemic adminstration of low doses of dopamine (DA) agonists other than by ACTH-MSH peptides. It has been suggested that DA agonists may induce such responses by releasing an ACTH-derived peptide from the pituitary gland. Recently, it has been discovered that the neonatal administration of monosodium glutamate (MSG) induces the almost complete depletion of ACTH, a-MSH and b-endorphin in the rat hypothalamus, providing a useful model to study the function of these peptides in brain. It has been also shown that hypophysectomy, that eliminates circulating ACTH, a-MSH and b-endorphin without altering their concentration in the hypothalamus, reduces penile erection and yawning induced not only by apomorphine, but also by ACTH 1-24. Two main conclusions derive from the above findings:
  • (1) an intact pituitary function is needed for the expression of the above responses of both ACTH and apomorphine, and
  • (2) apomorphine apparently does not induce penile erection and yawning by releasing an ACTHderived peptide from the pituitary gland.
However, the possibility remains that apomorphine induces yawning and penile erection by releasing an ACTH-derived peptide from central opiomelanotropinergic neurons. In an attempt to clarify the role of hypothalamic ACTH-MSH peptides in the expression of penile erection and yawning, we have studied the effect of ACTH 1-24 and apomorphine on the above responses in neonatally MSG-treated rats. [...]
 
DISCUSSION
The present results show that the depletion of hypothalamic ACTH and a-MSH by neonatal MSG treatment does not modify yawning and penile erection induced by ICV ACTH 1-24 or by low doses of systemic apomorphine. The reduced growth of MSG-treated rats, that is secondary to the destruction of hypothalamic growth hormone releasing hormone, seems not to be important for the expression of ACTH- and apomorphine-induced responses. In contrast, penile erection and yawning induced either by ACTH 1-24 or by apomorphine, were prevented by hypophysectomy, in agreement with previous studies. Taken together, the prevention of ACTH-induced yawning and penile erection by hypophysectomy and the ineffectiveness of hypothalamic ACTH-MSH depletion by MSG to alter ACTH-induced effect, indicate that an intact pituitary function rather than the integrity of hypothalamic ACTH-MSH-containing neurons, is important for the induction of yawning and penile erection by ACTH-MSH peptides. As previously discussed, this suggests that the pituitary gland exerts a permissive role in the expression of ACTH- and apomorphine-induced penile erection and yawning. In agreement with this hypothesis, hypophysectomy has been found to cause a marked decrease in central behavioural effects induced by other neuropeptides, and this decrease was completely prevented by the combined administration of testosterone, corticosterone and growth hormone.
 
On the other hand, previous studies have shown that hypophysectomy does not modify excessive grooming induced by ACTH, indicating that such responses might be mediated by a different mechanism. However, the above studies were performed in 5 days hypophysectomized rats, while one month hypophysectomized rats were used in the present study. Therefore, it is possible that the failure of hypophysectorny to mqdify ACTH-induced grooming was due to the short post-operative period used in the previous study.
 
The failure of hypothalamic ACTH-MSH depletion to modify ACTH-induced yawning and penile erection is surprising. Indeed, if yawning, stretching and penile erection after ICV ACTH are really due to the stimulation of brain ACTH-MSH receptors, one would expect a compensatory increase in the sensitivity of these receptors, but this was not observed. In agreement with the present study, neonatal MSG treatment was found to be unable to modify excessive grooming induced by ACTH and to induce significant changes in opiate receptors. Moreover, an attenuated analgesic response to morphine and a significant reduction in the stress-induced prolactin release have been shown in MSG-treated rats. However, these changes suggest a decreased rather than an increased sensitivity to opiates and ACTH-MSH peptides.
 
The inability of neonatal MSG treatment to modify apomorphine-induced penile erection and yawning suggests that apomorphine and other DA-agonists do not induce such responses by releasing an ACTH-derived peptide from central ACTH-MSH containing neurons. Thus, although both apomorphine and ACTH-derived peptides induce penile erection and yawning, it is possible that they act by a different mechanism or at different steps in the neuronal circuitry involved in the expression of these responses. If really apomorphine and ACTH act one after the other to induce yawning and penile erection, it is likely that the site of action of ACTH-derived peptides is situated after that of apomorphine, since ACTH-induced response is not antagonized by doses of neuroleptic drugs that completely prevent apomorphine-induced response.
 
Recently, we have found that the ICV injection of nanogram amounts of oxytocin induces penile erection and yawning in male rats. The powerful effect of oxytocin in eliciting the above responses, together with the presence of this neuropeptide in brain neurons in addition to the posterior pituitary, raises the possibility that apomorphine and/or ACTH-derived peptides induce penile erection and yawning by releasing oxytocin in some brain area or vice versa. The failure of neonatal MSG treatment to modify significantly the hypothalamic concentration of oxytocin leads us to speculate that apomorphine induces penile erection and yawning by releasing oxytocin in brain. Accordingly, both penile erection and yawning induced by oxytocin or apomorphine, but not by ACTH 1-24, have been found to be prevented by the ICV injection of the oxytocin antagonist d(CHA, Tyr-(Me)-Oml vasotocin.
 
In conclusion, although the possibility that ACTH-MSH peptides induce the above responses by acting in some extrahypothalamic brain area where they are not depleted by neonatal MSG treatment cannot by completely ruled out, the depletion of hypothalamic ACTH and a-MSH does not alter penile erection and yawning induced by ACTH 1-24 and apomorphine.