Overview of the mechanism of action of lithium in the brain: Fifty-year update

Since its discovery, lithium has been shown to act upon various neurotransm itter systems at multiple levels of signaling in the brain. Lithium, affect ing each neurotransmitter system within complex interactive neuronal networ ks, is suggested to restore the balance among aberrant signaling pathways i n critical regions of the brain. Recent molecular studies have revealed the action of lithium on signal transduction mechanisms, such as phosphoinosit ide hydrolysis, adenylyl cyclase, G protein, glycogen synthase kinase-3 bet a, protein kinase C, and its substrate myristoylated alanine-rich C kinase substrate. Such effects are thought to trigger long-term changes in neurona l signaling patterns that account for the prophylactic properties of lithiu m in the treatment of bipolar disorder. Through its effects on glycogen syn thase kinase-3 beta and protein kinase C, lithium may alter the level of ph osphorylation of cytoskeletal proteins, which leads to neuroplastic changes associated with mood stabilization. Chronic lithium regulates transcriptio nal factors, which in turn may modulate the expression of a variety of gene s that compensate for aberrant signaling associated with the pathophysiolog y of bipolar disorder. Future studies on long-term neuroplastic changes cau sed by lithium in the brain will set the stage for new drug-discovery oppor tunities.