title: Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders.
abstract: There exists an immediate need to develop novel medications for the treatment of mood disorders such as bipolar disorder and depression. Initial interest in glycogen synthase kinase-3 (GSK-3) as a target for the treatment of mood disorders arose from the finding that the mood stabilizing drug lithium directly inhibited the enzyme. More recent preclinical evidence implicates the modulation of GSK-3 in either the direct or downstream mechanism of action of many other mood stabilizer and antidepressant medications currently in use. One of the cellular targets of GSK-3, which may mediate some of the effects of lithium and other drugs, is beta-catenin, a transcription factor that is rapidly degraded when GSK-3 is active. Recent rodent behavioral data (both genetic and pharmacological) supports GSK-3 representing a therapeutically relevant target of lithium. This includes antidepressant-like behavior in the forced swim test and antimanic-like response to amphetamine following administration of the GSK-3 inhibitor AR-A014418, a findings that is concomitant with an increase in brain beta-catenin. The evidence described in this review suggests that regulating GSK-3 may represent a target for novel medications to treat mood disorders.
authors.affiliation: Laboratory of Molecular Pathophysiology, National Institute of Mental Health, NIH, Bethesda, MD 20892-3711, USA. gouldt@mail.nih.gov
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Picchini
authors.forename: Haim
authors.initials: H
authors.lastname: Einat
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000201:enzymology*; D016503:Drug Delivery Systems / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D019964:Mood Disorders / Q000188:drug therapy* / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3