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 neurotransmitter systems at multiplelevels of signaling in the brain. Lithium, affecting each neurotransmitter system within complexinteractive neuronal networks, is suggested to restore the balance among aberrant signaling pathwaysin critical regions of the brain. Recent molecular studies have revealed the action of lithium on signaltransduction mechanisms, such as phosphoinositide hydrolysis, adenylyl cyclase, G protein, glycogensynthase kinase-3ן, protein kinase C, and its substrate myristoylated alanine-rich C kinase substrate.Such effects are thought to trigger long-term changes in neuronal signaling patterns that account forthe prophylactic properties of lithium in the treatment of bipolar disorder. Through its effects on glycogensynthase kinase-3ן and protein kinase C, lithium may alter the level of phosphorylation of cytoskeletalproteins, which leads to neuroplastic changes associated with mood stabilization. Chroniclithium regulates transcriptional factors, which in turn may modulate the expression of a variety ofgenes that compensate for aberrant signaling associated with the pathophysiology of bipolar disorder.Future studies on long-term neuroplastic changes caused by lithium in the brain will set the stage fornew drug-discovery opportunities.