AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test
The mechanism by which lithium exerts either its anti-manic or antidepressant effects remains to be fully elucidated. Although lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3) at concentrations that are relevant for treatment of bipolar disorder, it is unclear whether GSK-3-related mechanisms are responsible for its therapeutic effects in the treatment of this disease. We report that AR-A014418 (a selective GSK-3 inhibitor) induces behavioural changes that are consistent with the effects of antidepressant medications. Subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, a well-established model for antidepressant efficacy. In addition, the specificity of this effect is supported by our finding that AR-A014418 decreased spontaneous as well as amphetamine-induced activity. Taken together, these data support the hypothesis that lithium may exert its antidepressant effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may be useful for the treatment of bipolar disorder and depression.(Received April 20 2004)
(Reviewed May 19 2004)
(Revised May 20 2004)
(Accepted May 26 2004)
Key Words: Behaviour; depression; forced swim test; glycogen synthase kinase-3; mania; manic-depressive illness.
c1 Dr H. K. Manji, Laboratory of Molecular Pathophysiology, NIMH, NIH, 9000 Rockville Pike, Bldg 35, Room 16-912, Bethesda, MD 20892-3711, USA. Tel.: 301 496-9802 Fax: 301 480-0123 E-mail: firstname.lastname@example.org
1 These authors contributed equally to this work.