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

Todd D. Gould , Haim Einat , Ratan Bhat , Husseini K. Manji
DOI: http://dx.doi.org/10.1017/S1461145704004535 387-390 First published online: 1 December 2004

Abstract

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.

Key words
  • Behaviour
  • depression
  • forced swim test
  • glycogen synthase kinase-3
  • mania
  • manic-depressive illness