INVOLVEMENT OF NEUROSTEROIDS IN THE EFFECT OF THE ENDOGENOUS BENZODIAZEPINE RECEPTOR-LIGAND OCTADECANEUROPEPTIDE (ODN) ON GONADOTROPIN-RELEASING-HORMONE GENE-EXPRESSION IN RAT-BRAIN

We have recently demonstrated that different activators of the GABA(A) receptor complex including reduced progesterone metabolites and the e ndozepine octodecaneuropeptide (ODN) exert an inhibitory influence on GnRH gene expression. In order to investigate the possible involvement of neurosteroids, especially progesterone metabolites in the effect o f ODN, we have evaluated in adrenalectomized and castrated male rats t he influence of pretreatment with an inhibitor of 3 beta-hydroxysteroi d dehydrogenase (3 beta-HSD) trilostane (TRIL) and an inhibitor of 5 a lpha-reductase MK-906 on GnRH mRNA levels in ODN-treated rats. TRIL co mpletely prevented the inhibitory influence of ODN on GnRH mRNA. It wa s also found that the inhibitor of 3 beta-HSD as well as pregnenolone sulfate (PREG-S), which has been shown to be increased following TRIL treatment, could induce an increase in GnRH mRNA. MK-906 could also co mpletely reverse the negative influence of ODN. When administered alon e, this antagonist of 5 alpha-reductase induced an increase in GnRH mR NA. These results clearly indicate that the inhibition of two key enzy mes for the synthesis of reduced progesterone metabolites can complete ly prevent the inhibitory influence of the endozepine ODN, suggesting that the effect of this endogenous ligand might be completely or parti ally mediated by an activation of the synthesis of active progesterone metabolites. On the other hand, it remains possible that, as a conseq uence of enzymatic inhibition, an increase in some precursors known as antagonists of GABA(A) may play a role in the prevention of the ODN e ffect by the two enzyme antagonists.