The pharmacology of adenylyl cyclase modulation by GABA B receptors in rat brain slices

Abstract

GABA B receptor activation inhibits forskolin-stimulated adenylyl cyclase activity but augments noradrenaline-stimulated adenylyl cyclase activity. The present study investigated the pharmacology of these two GABA B receptor mediated responses. In a cross-chopped rat cortical slice preparation, it was confirmed that (−)baclofen inhibited forskolin-stimulated adenylyl cyclase activity and augmented noradrenalinestimulated adenylyl cyclase activity. The potency of five further agonists was investigated (SKF97541, CGP47656, CGP44533, 3-APA and CGP44532). Of these agonists two compounds were significantly more potent as inhibitors of forskolin-stimulated adenylyl cyclase than as augmenters of noradrenaline-stimulated adenylyl cyclase activity, these were (−)baclofen ( p EC 50 = 6.07 ± 0.29 and 5.04 ± 0.17, respectively ( p < 0.05)), and CGP47656 (pEC 50 = 6.44 ± 0.05 and 4.48 ± 0.26, respectively ( p < 0.05)). It is possible to explain this difference in potency by proposing that these compounds have low intrinsic efficacy, and the augmentation of noradrenaline-stimulated adenylyl cyclase has a low receptor reserve. In addition six antagonists (CGP49311A, CGP46381, CGP45024, CGP35348, CGP45397, CGP36742) were also tested for their ability to antagonize 30 μM (−)baclofen in these two assays. These antagonists 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 pharmacologically similar receptors.