Further studies on the mechanism of action of the endogenous benzodiazepine receptor ligand octadecaneuropeptide on gonadotropin-releasing hormone gene expression in the rat brain.

Abstract

We have recently reported that the intracerebroventricular injection of the endogenous benzodiazepine (BZD) receptor ligand octadecaneuropeptide (ODN) (30 micrograms/kg b.w.) could induce a decrease in gonadotropin-releasing hormone (GnRH) mRNA levels in the male rat brain. This inhibitory effect could be completely reversed by the concomitant administration of the GABAA antagonist picrotoxin. In order to further investigate the mechanism of action of ODN, we investigated the effects of intracerebroventricular injection of a smaller dose of ODN (3 micrograms/kg b.w.) and the influence of the GABAA receptor agonist muscimol and the antagonist to BZD receptors flumazenil on GnRH gene expression. Treatment with ODN induced a 40% decrease in mRNA levels, an effect which was potentiated by the concomitant administration of muscimol. The administration of flumazenil produced a small increase in GnRH mRNA while the inhibitory effect of ODN on GnRH mRNA levels was completely prevented by the administration of this BZD antagonist. Moreover, the intravenous administration of increasing doses of ODN also induced a marked decrease of 33, 32 and 38% for 75, 150 and 300 micrograms/kg b.w., an effect which was completely abolished by picrotoxin. These data clearly indicate that an endogenous neuropeptide can activate the GABAA BZD receptor complex to negatively modulate the activity of GnRH neurons. They also suggest that this peptide or other endogenous activators of the GABAA BZD receptors might exert a tonic inhibitory influence on GnRH gene expression.