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This study found that (a) administration of a relatively low dose of ketamine to mice inhibits brain glycogen synthase kinase-3 (GSK3), (b) this inhibition of GSK3 is necessary for rapid antidepressant-like effect of ketamine in the mouse model of learned helplessness because mice expressing constitutively active GSK3 are completely resistant to the antidepressant-like effect of ketamine, and (c) administration of a dose of the GSK3 inhibitor lithium much higher than usually used produces a rapid antidepressant-like effect equivalent to ketamine. This demonstrates that inhibition of GSK3 is required for rapid antidepressant effect of ketamine in this model and raises the possibility that acute administration of specific GSK3 inhibitors may be sufficient to produce rapid antidepressant effects similar to ketamine.

Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice