INHIBITORY EFFECT OF THE POTENTIAL ENDOGENOUS BENZODIAZEPINE RECEPTOR-LIGAND, OCTADECANEUROPEPTIDE (ODN), ON GONADOTROPIN-RELEASING-HORMONE GENE-EXPRESSION IN THE MALE-RAT BRAIN

IT has been reported that activation of the GABA(A) receptor complex by different agents such as barbiturates and neurosteroids can negatively regulate the hypothalamopituitary-gonadal axis. Recently, an 86-amino acid polypeptide with high affinity for diazepam binding sites, termed diazepam-binding inhibitor (DBI), has been found in the rat brain. DBI as well as a peptide derived from DBI, the octadecaneuropeptide DBI[33-50] (ODN), can interact with the GABA(A) receptor complex. In order to investigate the role of these endogenous ligands for GABA(A) receptors on GnRH gene expression, we studied the effects of the acute administration (4 h before sacrifice) of ODN injected alone or in combination with the GABA(A) agonist muscimol on GnRH mRNA levels. Treatment with ODN produced a 31% decrease in the number of silver grains overlying labelled neurones. This effect was not modified by the concomitant administration of muscimol. The administration of the GABA(A) antagonist picrotoxin not only reversed the inhibitory effect of ODN but induced a 24% increase in the hybridization signal. This stimulating influence of picrotoxin was less striking (15% over control levels) when muscimol was administered with ODN. These data clearly indicate that a potential endogenous a neuropeptide can positively interact with the GABA(A) receptor complex to modulate GnRH neuronal activity.