GABA(B) RECEPTORS MODULATE CATECHOLAMINE SECRETION IN CHROMAFFIN CELLS BY A MECHANISM INVOLVING CYCLIC-AMP FORMATION

1 The function of gamma-aminobutyric acid(B) (GABA(B)) receptors in mo dulation of catecholamine secretion by chromaffin cells and the possib le mechanism involved in this action have been examined. 2 The GABA(B) agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secre tion. The EC50s were 151 +/- 35 muM and 225 +/- 58 muM for baclofen an d 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABA(B) antagonist CGP-3534 8. 3 In contrast, preincubation of chromaffin cells with the GABA(B) a gonists was found to inhibit, in a dose-dependent manner, the catechol amine secretion evoked by 10 muM nicotine and 200 muM muscimol. 4 The effects of GABA(B) agonists on both basal and evoked catecholamine sec retion were found to be accompanied by parallel changes in intracellul ar calcium concentration ([Ca2+]i). GABA(B) agonists produced a dose-d ependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5 The GABA(B) agonists also produced a dose -dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion an d in intracellular cyclic AMP levels. 6 The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and in creased by four times the intracellular cyclic AMP levels evoked by GA BA(B) agonists. 7 The possible involvement of adenylate cyclase in the mechanism of GABA(B) receptor modulation of catecholamine secretion i s discussed.