CENTRAL-TYPE BENZODIAZEPINES INHIBIT RELEASE OF ALPHA-MELANOCYTE-STIMULATING HORMONE FROM THE RAT HYPOTHALAMUS

In a previous work, we have shown that GABA inhibits the release of alpha-melanocyte-stimulating hormone (alpha-melanotropin) from hypothalamic neurons through activation of GABA(A) receptors [Delbende et al. (1989) Brain Res. 497, 86-93]. Since GABA-gated channel activity can be allosterically modulated by a variety of compounds including benzodiazepines, we have investigated the effect of benzodiazepines in the control of alpha-melanotropin release by the rat basal hypothalamus. This study was conducted in vitro using perifused rat hypothalamic slices and the amount of alpha-melanotropin release was monitored with a sensitive and highly specific radioimmunoassay. Infusion of clonazepam (50-mu-M), a selective agonist for central-type benzodiazepine binding sites, induced an inhibition of KCl (50 mM)-evoked alpha-melanotropin release. The inhibitory effect of clonazepan was rapid and reversible. Administration of Ro 15-1788 (100-mu-M), a specific antagonist for central-type benzodiazepine receptors or SR 95531, a GABA(A) receptor antagonist, completely reversed the inhibitory effect of clonazepam. In addition, Ro 15-1788 and SR 95531 both enhanced the amplitude of the response observed during prolonged KCl infusion on alpha-melanotropin neurons, suggesting the existence of a tonic inhibitory effect of endogenous GABA and/or benzodiazepines in the release of alpha-melanotropin by hypothalamic neurons. To investigate further the effect of benzodiazepines in the regulation of alpha-melanotropin neurons, rats were treated in vivo with clonazepam (5 mg/kg) or the non-selective benzodiazepine receptor agonist diazepam (3 mg/kg). Both compounds caused a significant increase in the content of alpha-melanotropin and beta-endorphin in the rat hypothalamus within 3 h. At the pituitary level, diazepam induced a significant increase of alpha-melanotropin and beta-endorphin concentrations in the neurointermediate lobe and corticotropin concentration in the anterior lobe. In contrast, clonazepam had no effect on peptide concentrations in the neurointermediate lobe and slightly increased corticotropin level in the anterior pituitary. Altogether, these results indicate that benzodiazepines exert an inhibitory control on the release of alpha-melanotropin from hypothalamic neurons via modulation of the GABA(A) receptor complex. In contrast, the action of benzodiazepines on alpha-melanotropin-related hormones at the pituitary level appears to be mainly mediated through peripheral-type benzodiazepine receptors.