EFFECTS OF CHRONIC LITHIUM TREATMENTS ON CENTRAL DOPAMINERGIC RECEPTOR SYSTEMS - G-PROTEINS AS POSSIBLE TARGETS

Numerous biochemical and electrophysiological studies have proposed a role for dopamine (DA) in the therapeutic efficacy of lithium (Li+) sa lts. The effects of ex vivo chronic Li+ treatments on neostriatal DA r eceptors, as well as on the G protein adenylyl cyclase complex and on tissue cAMP levels were investigated in adult rats. The animals were a dministered LiCl in their drinking water (1 g/l) for varying periods o f time, i.e. 1, 15 and 28 days. After sacrifice by decapitation, their brains were removed and the neostriatum dissected out to assay DA rec eptors and adenylyl cyclase activity. The antagonists [H-3]SCH23390 an d [H-3]raclopride were employed to label D1 and D2 receptors, respecti vely. Chronic Li+ treatments did not modify the saturation binding of either ligand. However, competition studies of the same antagonists by DA revealed biphasic curves, and the inhibition constant of the high- affinity site was significatively increased after chronic Li+. The dat a suggest an alteration in the coupling efficacy between G proteins an d DA receptors. Moreover, chronic (28 day) Li+ treatment, but not a 1 day Li+ administration, lead to a reduction of the GTP-induced and DA- sensitive adenylyl cyclase activity, without changes in the basal acti vity or in forskolin-induced cAMP production. The results demonstrate that chronic Li+ treatments diminish neostriatal dopaminergic activity , probably through a direct action on the G protein itself. The underl ying mechanisms do not appear to involve modifications in either the D 1 or the D2 receptor primary ligand recognition sites, but may represe nt alterations in both the coupling process and the capacity of the G proteins, once activated. to stimulate adenylyl cyclase.