Muscarinic involvement in the regulation of gonadotropin-releasing hormone in the cyclic rat.

The release of gonadotropin-releasing hormone (GnRH) from the median eminence (ME) in cyclic rats was stimulated to a significant extent by the selective muscarinic antagonists 11[(2)(diethylamino)methyl][-1-piperidinyl]-acetyl-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX-116) and methoctramine, and to a lesser extent also by other ligands selectively antagonistic to m1 and m3 receptors. Such stimulation was estrous-cycle-dependent and was not achieved by muscarinic agonists. We suggest that the effect is induced via the m4 receptor subtype. Attempts to block the muscarinic-antagonist-induced stimulation of GnRH release with a variety of drugs were successful only in the presence of prazosin, an antagonist to alpha 1-adrenergic receptors. One possible explanation for this muscarinically mediated stimulation of GnRH release is that it results from cross-talk between the muscarinic and the alpha 1-adrenergic receptors, i.e., muscarinic agonists might inhibit the release induced by alpha 1-agonists, and muscarinic antagonists, by cancelling this inhibitory effect, might thus allow the endogenous alpha 1-agent, norepinephrine, to induce the release of GnRH.