Evidence for different interactions between beta(1)- and beta(2)-adrenoceptor subtypes with adenylyl cyclase in the rat brain: A concentration-response study using forskolin

The aim of this study was to investigate beta(1)- and beta(2)-adrenoceptor signalling systems in the rat brain studying the synergistic effects betwee n beta-adrenoceptor agonists and forskolin-induced activation of adenylyl c yclase. Experiments were performed in slices from cerebral cortex and cereb ellum because they contain mainly beta(1)- and almost exclusively beta(2)- adrenoceptors? respectively. Five beta-adrenergic agonists were used, clenb uterol, flerobuterol, isoproterenol, salbutamol, and tulobuterol. All agoni sts stimulated cyclic AMP accumulation in the cerebral cortex but flerobute rol was inactive in the cerebellum Forskolin amplified the generation of cy clic AMP. Forskolin potentiation was observed in glial cells but not in neu rons and was not dependent on the number of beta-adrenoceptors. In return t he amplitude of the potentiation was highly dependent on the intrinsic acti vity of the agonist in the cerebral cortex whereas it was constant whatever the agonist tested in the cerebellum. To analyse this difference we develo ped a modelling approach using a concentration-response study. Isoprotereno l and forskolin stimulations of cyclic AMP production were studied either a lone or in combination with increasing concentrations of forskolin and isop roterenol, respectively. In the cerebral cortex isoproterenol and forskolin were both able to potentiate the cyclic AMP accumulation induced by the ot her compound, whereas, in the cerebellum, isoproterenol was unable to incre ase the stimulation induced by forskolin. The results support the hypothesi s that beta(1)- and beta(2)-adrenoceptors display distinct mechanisms of ac tion in the signalling system by which they stimulate the accumulation of c yclic AMP. (C) 2000 Academic Press.