Interaction between GABAergic neurotransmission and rat hypothalamic corticotropin-releasing hormone secretion in vitro

Abstract

Corticotropin-releasing hormone (CRH) has been considered a major coordinator of the overall physical and behavioral response to stress. Moreover, prolonged hypersecretion of CRH has been implicated in the pathogenesis of disorders characterized by anxiety and/ or depression. Drugs acting through the γ-aminobutyric acid/benzodiazepine (GABA/BZD) receptor system have anxiolytic and/or antidepressant properties whereas benzodiazepine inverse agonists cause anxiety and stimulate the pituitary-adrenal axis in vivo. To examine the involvement of the GABA/BZD system in the regulation of hypothalamic CRH secretion, we studied the effects of various agonists and antagonists of GABA A and GABA B receptors using a sensitive rat hypothalamic organ culture with radioimmunoassayable CRH (IR-rCRH) as endpoint. The GABA A and GABA B receptor agonist GABA inhibited serotonin (5-HT)-induced IR-rCRH secretion from 10 −9 to 10 −6 M, but failed to do so at 10 −5 M. The GABA A receptor agonist muscimol was a weak inhibitor of 5-HT-induced IR-rCRH secretion, being effective only at the concentration of 10 −6 M. In contrast, the specific GABA B receptor agonist baclofen was able to inhibit 5-HT-induced IR-rCRH secretion from 10 −7 to 10 −5 M. The rank of potency was thus, GABA > baclofen > muscimol. Bicuculine, a GABA A receptor antagonist, partially reversed the inhibitory effects of GABA. Diazepam, a classic benzodiazepine which interacts with the benzodiazepine-site of the GABA A receptor complex, inhibited 5-HT-induced IR-rCRH secretion from3.3 × 10 −9to 10 −5 M, an effect that could be reversed the BZD inactive ligand Ro15-1788. The diazepam inverse agonist γ-carboline-3-carboxylic acid methylester was a potent stimulator of IR-rCRH secretion and its effect was antagonized only by high concentrations of diazepam but not by Ro15-1788. These results suggest that the GABA/BZD system is involved in the regulation of CRH secretion. It appears that both GABA A and GABA B receptors mediate the suppressive effects of GABA upon 5-HT-induced CRH secretion. We speculate that drugs acting through the GABA/BZD system may exert, at least in part, their anxiolytic and/or antidepressant effects via suppression of central CRH secretion.