Pharmacological modulation of adrenal medullary GABAA receptor: consistent with its subunit composition

Abstract

1. Muscimol, the specific GABAA receptor agonist, increased the secretion of catecholamines by chromaffin cells with an EC50 of 2.9 +/- 0.4 microM. 2. GABAA receptors of these cells were modulated by the same drugs which modulate GABAA receptors in brain tissue. 3. Benzodiazepines enhanced muscimol-evoked catecholamine secretion by between 20 and 80%. This effect seems to be mediated by binding to a central type of benzodiazepine receptor because it was completely blocked by the specific antagonist, Ro 15 1788. This antagonist was able to displace [3H]-flunitrazepam binding with an EC50 of 0.26 +/- 0.05 nM. 4. beta-Carbolines weakly inhibited muscimol-induced catecholamine secretion and were able to displace [3H]-flunitrazepam binding with an EC50 between 0.2 and 0.9 nM, depending on the beta-carboline used. 5. Pregnanolone and related neuroactive steroids enhanced muscimol-evoked catecholamine secretion by up to 87%, in a dose-dependent fashion. In contrast pregnenolone weakly inhibited muscimol-evoked catecholamine secretion. 6. Zn2+ did not affect GABAA receptor-induced catecholamine secretion. 7. These pharmacological results are absolutely concordant with the theoretical properties given by the GABAA receptor subunit composition of bovine adrenal medulla -alpha 1, alpha 4, beta 1-3, gamma 2-previously characterized by Western blot analysis.