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.
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-3711, USA.
Todd D
TD
Gould
Haim
H
Einat
Ratan
R
Bhat
Husseini K
HK
Manji
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming / Q000523:psychology*; D013844:Thiazoles / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000928:Antidepressive Agents; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D013844:Thiazoles; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D000661:Amphetamine; D038362:Glycogen Synthase Kinase 3