The octadecaneuropeptide-induced response of corticotropin-releasing hormone messenger RNA levels is mediated by GABA A receptors and modulated by endogenous steroids

The involvement of endogenous benzodiazepine octadecaneuropeptide in the regulation of corticotropin-releasing hormone messenger RNA expression has been studied using in situ hybridization technique. Intracerebroventricular injection of octadecaneuropeptide (4 μg/kg) induced a 26% decrease in the corticotropin-releasing hormone messenger RNA expression in the hypothalamic paraventricular nucleus. Concomitant injection of octadecaneuropeptide and i.p. injection of the GABA A receptor agonist muscimol (4 mg/kg) potentiated the corticotropin-releasing hormone messenger RNA decrease (−34%). The depressing effect of octadecaneuropeptide on corticotropin-releasing hormone gene expression was totally reversed by pretreatment of the animals with the GABA A receptor antagonist picrotoxin (5 mg/kg; i.p.) or by pretreatment with the benzodiazepine receptor antagonist flumazenil (4 mg/kg; i.p.). To determine the reciprocal involvement of adrenal and sexual steroids in this regulation, animals are adrenalectomized and/or castrated. Adrenalectomy reversed the effect induced by octadecaneuropeptide, which increased corticotropin-releasing hormone messenger RNA expression (+21%), while castration did not modify the negative influence of octadecaneuropeptide. When rats were adrenalectomized and castrated, the adrenalectomy influence was predominant, since octadecaneuropeptide increased significantly the hybridization signal (+18%). The involvement of neurosteroids, especially reduced metabolites of progesterone was also investigated. The concomitant injection of octadecaneuropeptide and subcutaneous injection of the 5 α-reductase inhibitor MK-906 (14 mg/kg) to adrenalectomized and castrated rats, reduced significantly by 60% the increase of corticotropin-releasing hormone messenger RNA expression induced by octadecaneuropeptide. These results indicate that in vivo the endogenous benzodiazepine octadecaneuropeptide, via an activation of the benzodiazepine sites of the GABA A receptor, negatively modulates corticotropin-releasing hormone neuronal activity and that this modulation can be negatively or positively influenced by central and peripheral steroids.