INTRINSIC GAMMA-AMINOBUTYRIC-ACID RECEPTORS MODULATE THE RELEASE OF CATECHOLAMINE FROM CANINE ADRENAL-GLAND INSITU

Abstract

Immunohistochemical analysis documented the presence of .gamma.-aminobutyric acid (GABA)-containing fibers and GABA-containing chromaffin cells in canine adrenal glands. A dense network of fibers was visualized at the boundary between medullary and cortical cells, and, in the medullary tissue, GABA-containing fibers surrounded chromaffin cells. Some of these fibers enter the adrenal medulla together with splanchnic cholinergic nerves. The functional role of the GABAergic system in the regulation of catecholamine release from adrenal chromaffin cells was studied in canine adrenal glands in situ, using an autoperfusion system for the adrenal gland that was designed to eliminate indirect central effects of drugs or their metabolites on catecholamine release. The present study documents that GABA modulates the spontaneous release of catecholamines and the release elicited by electrical stimulation of the splanchnic nerve. GABAA receptor agonists such as THIP or muscimol increased the catecholamine content in adrenal effluent blood, whereas bicuculline (0.05 mmol/2 ml min-1), a GABAA receptor antagonist, reduced it. Baclofen (0.094 mmol/2 ml min-1), a GABAB receptor agonist, failed to alter the catecholamine content in adrenal effluent blood. The increased release of catecholamines elicited by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3[2H]-one. (THIP; 0.143 mmol/2 ml min-1) was prevented by bicuculline (0.05 mmol/2 ml min-1) but not by hexamethonium (2.48 mmol/2 ml min-1) or naloxone (0.122 mmol/2 ml min-1). Furthermore, denervation of the adrenal glands failed to prevent the THIP-elicited release of catecholamines. These data suggest that THIP released catecholamines through direct stimulation of GABAA receptors located on chromaffin cell membranes, presumably by causing a burst of Cl- channel opening whereby Cl- could flow extracellularly and elicit membrane depolarization. The present data also showed that the extent of catecholamine release elicited by splanchnic nerve stimulation was decreased by administration of THIP (1 mg/kg i.v.) and was increased by bicuculline (1 mg/kg i.v.). These data showing that GABAA receptor agonists inhibit the release of catecholamines elicited by nicotinic receptor stimulation suggest that endogenous GABA may reduce the responsiveness of nicotinic receptors on chromaffin cells.