The International Journal of Neuropsychopharmacology

Rapid Communication

AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test

Todd D. Gould a1 1 , Haim Einat a1 1 , Ratan Bhat a2 and Husseini K. Manji a1c1
a1 Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
a2 AstraZeneca R&D Södertälje, Sweden

Article author query
gould td   [PubMed][Google Scholar] 
einat h   [PubMed][Google Scholar] 
bhat r   [PubMed][Google Scholar] 
manji hk   [PubMed][Google Scholar] 


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:


1 These authors contributed equally to this work.