REGULATION OF PROOPIOMELANOCORTIN GENE-EXPRESSION BY ENDOGENOUS LIGANDS OF THE GABA(A) RECEPTOR COMPLEX AS EVALUATED BY IN-SITU HYBRIDIZATION IN THE RAT PARS-INTERMEDIA

The neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inh ibitory influence on proopiomelanocortin (POMC) neurons in the hypotha lamus as well as on the melanotrope cells of the intermediate lobe (IL ) of the pituitary gland. Moreover, the activation of the GABA(A) rece ptor complex by different ligands has been shown to exert a negative i nfluence on the POMC gene expression at the hypothalamic level. In ord er to elucidate the in vivo regulation of the POMC mRNA levels in the intermediate lobe of the pituitary by endogenous ligands of the GABA(A ) receptor complex, we have studied the effect of intravenous (i.v.) a nd intracerebroventricular (i.c.v.) injections of octadecaneuropeptide (ODN), a peptide derived from diazepam-binding inhibitor (DBI). The p ossible involvement of neurosteroids in the action of ODN on melanotro pic cells was evaluated following inhibition of two enzymes involved i n the biosynthesis of neurosteroids known as activators of G3BA(A) rec eptor complex: trilostane, an inhibitor of 3 beta-hydroxysteroid dehyd rogenase (3 beta-HSD), and MK-906, an inhibitor of 5 alpha-reductase. The i.v. injection of ODN produced a dose-dependent inhibition of POMC gene expression in the IL. The i.c.v. injection of ODN also depressed POMC mRNA. These effects were completely reversed by the concomitant administration of the GABA(A) antagonist picrotoxin. Similar results w ere obtained in POMC neurons in the arcuate nucleus (AN) of the hypoth alamus. Trilostane administration induced an increase in POMC mRNA and also prevented the inhibitory influence of ODN. The neurosteroid preg nenolone-sulfate, a negative modulator of the GABA(A) receptor, also s timulated POMC gene expression. On the other hand, MK-906 produced a d ecrease in mRNA levels and could not reverse the effect of ODN. The re sults indicate that activation of the GABA(A) receptor complex by the endogenous benzodiazepine receptor ligand ODN can induce a negative re gulation of POMC gene expression in the IL of the pituitary and neuron s in the AN. The present results do not provide clear evidence that ne urosteroids are involved in the action of ODN on POMC gene expression in the IL. (C) 1997 Elsevier Science B.V.