THE PHARMACOLOGY OF ADENYLYL-CYCLASE MODULATION BY GABA(B) RECEPTORS IN RAT-BRAIN SLICES

GABA(B) receptor activation inhibits forskolin-stimulated adenylyl cyc lase activity but augments noradrenaline-stimulated adenylyl cyclase a ctivity. The present study investigated the pharmacology of these two GABA(B) receptor mediated responses. In a cross-chopped rat cortical s lice preparation, it was confirmed that (-)baclofen inhibited forskoli n-stimulated adenylyl cyclase activity and augmented noradrenaline-sti mulated adenylyl cyclase activity. The potency of five further agonist s was investigated (SKF97541, CGP47656, CGP44533, 3-APA and CGP44532). Of these agonists two compounds were significantly more potent as inh ibitors of forskolin-stimulated adenylyl cyclase than as augmenters of noradrenaline-stimulated adenylyl cyclase activity, these were (-)bac lofen (PEC(50) = 6.07 +/- 0.29 and 5.04 +/- 0.17, respectively (p < 0. 05)), and CG47656 (PEC(50) = 6.44 +/- 0.05 and 4.48 +/- 0.26, respecti vely (p < 0.05)). It is possible to explain this difference in potency by proposing that these compounds have low intrinsic efficacy, and th e augmentation of noradrenaline-stimulated adenylyl cyclase has a low receptor reserve. In addition six antagonists (CGP49311A, CGP46381, CG P45024, CGP35348, CGP45397, CGP36742) were also tested for their abili ty to antagonize 30 mu M (-)baclofen in these two assays. These antago nists ranged in potency as inhibitors of forskolin-stimulated adenylyl cyclase activity from CGP49311A (pEC50 = 5.45 +/- 0.30) to CGP36742 ( pEC50 = 3.87 +/- 0.16). Each antagonist had similar potency in the two assays, suggesting that these two responses are mediated by pharmacol ogically similar receptors. Copyright (C) 1996 Elsevier Science Ltd.