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.
Gould
Todd D
TD
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-3711, USA.
Einat
Haim
H
Bhat
Ratan
R
Manji
Husseini K
HK
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