TY - JOUR T1 - A Negative Allosteric Modulator for alpha5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0285-16.2017 SP - ENEURO.0285-16.2017 AU - Panos Zanos AU - Mackenzie E. Nelson AU - Jaclyn N. Highland AU - Samuel R. Krimmel AU - Polymnia Georgiou AU - Todd D. Gould AU - Scott M. Thompson Y1 - 2017/02/21 UR - http://www.eneuro.org/content/early/2017/02/21/ENEURO.0285-16.2017.abstract N2 - 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 alpha 5 subunits (alpha5 GABA-NAMs) should also promote high frequency correlated EEG activity and should therefore exert rapid antidepressant responses. Because alpha 5 subunits display a restricted expression in the forebrain, we predicted that alpha5 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 alpha5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 hrs after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test. Like ketamine, MRK-016 produced a transient increase in EEG gamma power and both the increase in gamma power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist NBQX. Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of pre-pulse inhibition, no conditioned place preference, and no change in locomotion. alpha5 GABA-NAMs thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.Significance Statement: There is need for new, fast-acting antidepressant drugs. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions, but has many side effects. We predicted that drugs that weaken inhibitory synaptic transmission by modulating GABAA receptors containing alpha 5 subunits would exert rapid antidepressant effects, but cause fewer side effects because they act at one type of receptor with a restricted brain localization. Indeed, administration of an alpha5 GABA-NAM resulted in rapid and persistent antidepressant effects in several behavioral tests, and did not affect locomotion or motor performance, did not change a measure of psychosis susceptibility, and did not appear to have abuse potential. These compounds thus display great clinical promise as novel fast-acting antidepressants. ER -