Abstract
New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.
Footnotes
T.D.G. has received consulting fees from Sunovion Pharmaceuticals and Janssen Pharmaceuticals and research funding from Janssen Pharmaceuticals and Roche Pharmaceuticals during the preceding three years. T.D.G. and P.Z. are listed as coinventors on a patent application for the use of ketamine metabolites, (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine, in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. T.D.G. and P.Z. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. S.M.T. is listed as a coinventor on a patent application for the use of negative allosteric modulators of GABA-A receptors containing α5 subunits as fast-acting antidepressants. He has assigned his patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. M.E.N., J.N.H., S.R.K., and P.G. declare no competing financial interests.
This work was supported by National Institute of Health Grants NH086828 (to S.M.T.) and MH107615 (to T.D.G.) as well as by a gift from the Kahlert Foundation (S.M.T.).
↵‡ Gould and Thompson are co-senior authors.
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