Does the Effect of Lithium on G-Proteins Have Behavioral Correlates?

Abstract

Lithium is a unique treatment in psychiatry with both antidepressant and antimanic properties. The mode of action of lithium has not yet been clarified. Lithium has been shown to inhibit the accumulation of cyclic AMP stimulated by noradrenaline both in intact rat brain synaptosomes and in slices from rat cortex after in vitro or ex vivo administration (1,2). This effect occurs within the therapeutic range of the drug (0.7–1.5 mM) and has been proposed to account for its clinical efficacy (3). Hormone-sensitive adenylate cyclase activity is the result of the concerted function of a complex of at least three separate proteins: a hormone receptor, a catalyst, and a guanine nucleotide-binding protein (4). It is well established that beta-adrenergic-induced activation of adenylate cyclase is mediated by the stimulatory G-protein, Gs. Upon agonist binding, a quaternary complex is formed between agonist-occupied receptor and GTP-bound G-protein. Subsequently, the G-protein is dissociated into subunits (5). The alpha-s subunit activates adenylate cyclase while exhibiting GTP-ase activity. Several authors investigated lithium action on the various components along the hormone-activated adenylate cyclase pathway. Although lithium inhibits agonist-stimulated adenylate cyclase activity, it has been shown not to affect beta-adrenergic receptor density (6). Lithium was shown to inhibit Gpp (NH) p-stimulated adenylate cyclase activity in rat cerebral cortex (7).