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 multiple levels of signaling in the brain. Lithium, affecting each neurotransmitter system within complex interactive neuronal networks, is suggested to restore the balance among aberrant signaling pathways in critical regions of the brain. Recent molecular studies have revealed the action of lithium on signal transduction mechanisms, such as phosphoinositide hydrolysis, adenylyl cyclase, G protein, glycogen synthase kinase-3beta, 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 for the prophylactic properties of lithium in the treatment of bipolar disorder. Through its effects on glycogen synthase kinase-3beta and protein kinase C, lithium may alter the level of phosphorylation of cytoskeletal proteins, which leads to neuroplastic changes associated with mood stabilization. Chronic lithium regulates transcriptional factors, which in turn may modulate the expression of a variety of genes 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 for new drug-discovery opportunities.
Lenox
R H
RH
Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-6140, USA. rlenox@mail.med.upenn.edu
Hahn
C G
CG
D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008094:Lithium / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects; D009479:Neuropeptides / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D003598:Cytoskeletal Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D008094:Lithium; D011494:Protein Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins