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

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 gamma-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 GABAA and GABAB receptors using a sensitive rat hypothalamic organ culture with radioimmunoassayable CRH (IR-rCRH) as endpoint. The GABAA and GABAB 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 GABAA 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 GABAB 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 much greater than baclofen greater than muscimol. Bicuculline, a GABAA receptor antagonist, partially reversed the inhibitory effects of GABA. Diazepam, a classic benzodiazepine which interacts with the benzodiazepine-site of the GABAA receptor complex, inhibited 5-HT-induced IR-rCRH secretion from 3.3 X 10(-9) to 10(-5) M, an effect that could be reversed by the BZD inactive ligand Ro15-1788.(ABSTRACT TRUNCATED AT 250 WORDS)