ABSTRACT
Lithium is the gold standard treatment for bipolar disorder. Early studies on the mechanism of action of lithium focused on neurotransmitters and determined that the drug exerts effects on synthesis, turnover and release of monoaminergic neurotransmitters and their receptors in the central nervous system1-5. However, these effects occur only at supratherapeutic concentrations of lithium or after its acute administration. Because lithium must be administered chronically to influence the course of bipolar disorder and to prevent relapse of manic and depressive episodes, the drug’s acute biochemical effects are not able to lead to a conclusive understanding of its mechanism of action. Since intracellular signaling pathways play a pivotal role in the central nervous system, recent research into lithium’s mechanism of action has shifted from individual neurotransmitters and their receptors to focus on post-receptor events and mechanisms. Indeed, an increasing body of evidence has been
accumulated demonstrating that chronic treatment with lithium at therapeutically relevant concentrations affects G-proteins and their effectors, including cyclic AMP and phosphoinositide signaling pathways. Chronic lithium treatment has been reported in a variety of neuronal tissues and cells to increase the basal level of cyclic AMP, to decrease agonist-induced increases in guanosine triphosphate (GTP) binding and cyclic AMP level, to induce the translocation of cyclic AMP dependent protein kinase from the cytosol to the nucleus, to increase expression of specific adenylyl cyclase isoforms and phosphorylation of DARPP-32, a substrate for cyclic AMP-dependent protein kinase6-15.
