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

Molecular Psychiatry volume 16, pages 1068–1070 (2011)Cite this article

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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.

Ketamine administration can produce rapid antidepressant effects in patients with major depression and relieve treatment-resistant depression.1, 2 These actions likely arise from ketamine's antagonism of glutamatergic N-methyl-D-aspartate (NMDA) receptors, as well as from additional mechanisms that have been suggested.3, 4, 5 We previously found that memantine, another NMDA antagonist, caused rapid inhibition of glycogen synthase kinase-3 (GSK3) in mouse brain,6 which raised the possibility that ketamine may have a similar action. This is relevant because much evidence links inadequate inhibition of GSK3 to major depressive disorder and bipolar disorder.7 Here, we report that ketamine rapidly inhibits GSK3 in mouse brain, and the rapid antidepressant effect of ketamine in the learned helplessness model of depression-like behavior requires inhibition of GSK3 and is mimicked by acute high-dose administration of the GSK3 inhibitor lithium.

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  1. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

    E Beurel, L Song & R S Jope

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  1. E Beurel
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  2. L Song
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  3. R S Jope
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Correspondence to R S Jope.

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Beurel, E., Song, L. & Jope, R. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16, 1068–1070 (2011). https://doi.org/10.1038/mp.2011.47

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