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27 mai 2004
Brain Research Bulletin
1990; 24; 853-856
Role of calcium in the expression of ACTH-induced stretching, yawning and penile erection
A Argiolas, MR Melis, R Stancampiano, GL Gessa
BB Brodie Department of Neurosciences, University of Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


The intracerebroventricular (ICV) administration of adrenocorticotropin (ACTH) and related peptides induces a peculiar symptomatology characterized by recurrent episodes of stretching, yawning, penile erection and ejaculation in different experimental animals.
In rats, the symptomatology begins 25-30 min after the treatment and lasts for several hours. The reason for the delay in the onset of the effect and the mechanism by which ACTH acts in the central nervous system to induce these behavioral responses are unknown, although the hypothalamus is believed to be the brain site where the peptide acts to induce the above effects and pharmacological studies suggest that central cholinergic and opioid transmission are involved.
As to the physiological significance of these behavioral responses, while the importance of penile erection in reproduction does not need to be stressed, it is pertinent to recall that stretching and yawning have been considered to have the role of increasing attention when sleep is pressing in front of a danger or social circumstances. With the aim to clarify the mechanism by which ACTH and related peptides induce the above behavioral responses, we studied the effect of calcium channel blockade on ACM-induced stretching, yawning and penile ereclion. Furthermore, since penile erection and yawning can be also induced by the dopaminergic agonist apomorphine and oxytocin, the relationship among ACTH, dopamine and oxytocin in the expression of these behavioral responses was investigated.[...]
Discussion: The present results show that ACTH-induced stretching, yawning and penile erection are prevented in a dose-dependent manner by w-conotoxin, a rather potent and selective inhibitor of N-type calcium channels present mainly in the nervous tissues, but not by organic calcium channel inhibitors belonging to different chemical classes such as nimodipine, verapamil and flunarizine.
The finding suggests that ACTH induces the above behavioral responses by mobilizing calcium through N-type calcium channels in some neuronal population in brain. The involvement of the other types of calcium channels (i.e., L and T) in the expression of ACTH effects seems to be minor, being organic calcium channel inhibitors unable to modify ACTH responses. In contrast, the ability of both organic calcium channel inhibitors and of w-conotoxin to inhibit apomorphine- and oxytocin-induced yawning and penile erection suggests that L- or T-type calcium channels also other than those of the N-type play an important role in these behavioral responses induced by apomorphine and oxytocin.
Together the above findings suggest that ACTH induces yawning and penile erection by acting with a mechanism different from that of oxytocin and apomorphine. A similar conclusion is also supported by the ability of PVN w-conotoxin microinjections to prevent apomorphine and oxytocin effect but not that of ACTH.
This is in agreement with previous studies showing that ACTH acts by a mechanism not involving hypothalamic dopamine or oxytocin. Accordingly, while the PVN is the most sensitive brain area for the induction of penile erection and yawning by oxytocin and apomorphine, other hypothalamic brain areas are involved in the expression of ACTH-induced yawning, and ACTH-induced penile erection and yawning are prevented neither by dopaminergic antagonists nor by oxytocin antagonists nor by electrolytic lesions of the PVN. Conversely, apomorphine- and oxytocin-induced penile erection and yawning are prevented by oxytocin antagonists with a rank order that ows their potency in blocking oxytocin receptors but not by the depletion of hypothalamic ACTH-MSH-like peptides induced by neonatal treatment with monosodium glutamate, suggesting that, while apomorphine induces the above responses by releasing oxytocin in the central nervous system, neither apomorphine nor oxytocin effect are mediated by the release of an ACTH-like peptide in brain.
Other than those recalled above, three other important features distinguish ACTH-induced symptomatology from that induced by apomorphine or by oxytocin: the requirement of much higher doses (2-3 nmol ICV of ACTH 1-24 versus 10-50 pmol ICV of oxytocin or 40-80 µg/kg SC of apomorphine, respectively); a much longer delay in the onset of the effect (25-30 min for ACTH and 5-10 min for oxytocin and apomorphine, respectively); and a more long-lasting effect (several hours for ACTH and 45-60 min for apomorphine and oxytocin, respectively).
Our data support a role for calcium involvement in the expression of stretching, yawning and penile erection induced by ACTH-related peptides. As to the mechanism by means of which ACTH induces calcium mobilization, only some speculation is possible at present. One possibility is that ACTH directly activates calcium channels or influences one of the various biochemical systems known to modify calcium homeostasis, such as phosphoinositide turnover, ATPase activity or calcium binding to calmodulin-like proteins. In this regard it is noteworthy that ACTH and related peptides affect phosphatydilinositol metabolism in membrane fractions from rat brain, inhibit the activity of a brain protein kinase and consequently the calcium-dependent phosphorylation of its substrate proteins, and increases intracellular calcium concentration in target cells.
Other than those recalled above, ACTH and related peptides induce also other neurochemical and electrophysiological changes in the central nervous system. Namely, they increase neuronal firing, cyclic adenosine monophosphate (c-AMP) formation and increase acetylcholine and catecholamine transmission and acetylcholine turnover as well. These changes might be also involved in the expression of yawning, stretching and penile erection, since our data do not rule out the possibility that w-conotoxin blocks calcium channels at sites located downstream rather than upstream to these events. In view of the existence of a central opiomelanocorticotropinergic system originating in the hypothalamus and projecting to several extrahypothalamic brain areas, further studies are necessary to clarify the site where ACTH and related peptides act to induce these behavioral responses and other central effects as well
In conclusion, although more experiments are necessary to clarify the mechanism responsible for calcium mobilization, and to identify the site where this mobilization would occur, the present results suggest that calcium might be one of the second messenger which mediates stretching, yawning and penile erection induced by ACTH and related peptides.