Effects of lithium on the beta-adrenergic receptor-adenylate cyclase system in rat cerebral cortical membranes.

The effects of lithium on the beta-adrenoceptor-adenylate cyclase system in cerebral cortical membranes of rats were investigated. Lithium chloride inhibited adenylate cyclase activity in a concentration-dependent manner in vitro. However, relatively high concentrations of lithium were needed for this inhibition; and at 1 mM, no significant reduction in adenylate cyclase activity was seen under any condition. Administration of lithium carbonate for 21 days decreased the maximum number of [3H]dihydroalprenolol binding sites without changing the apparent dissociation constant. Activation of adenylate cyclase by (-)-isoproterenol in the presence of 1 microM guanyl-5'-ylimidodiphosphate (Gpp(NH)p) was significantly attenuated in lithium-treated rats compared with the controls. Lithium treatment reduced the Gpp(NH)p-stimulated adenylate cyclase activity in the presence of 10 microM (-)-isoproterenol, but not in the absence of this beta-adrenergic receptor agonist. Basal activity or adenylate cyclase activity stimulated by forskolin or manganese was not affected, whereas the activity stimulated by sodium fluoride was significantly attenuated by long-term lithium treatment. These results indicate that chronic lithium treatment induces subsensitivity in the beta-adrenoceptor-adenylate cyclase system, for which down-regulation of beta-adrenergic receptors is chiefly responsible.