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dc.contributor.authorZanos, P.
dc.contributor.authorNelson, M.E.
dc.contributor.authorHighland, J.N.
dc.date.accessioned2019-07-15T16:16:56Z
dc.date.available2019-07-15T16:16:56Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85029851700&doi=10.1523%2fENEURO.0285-16.2017&partnerID=40&md5=ac5a934ff1409ad04a0a11cc8bfbe971
dc.identifier.urihttp://hdl.handle.net/10713/10003
dc.description.abstractNew 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. Copyright 2017 Zanos et al.en_US
dc.description.urihttps://www.doi.org/10.1523/ENEURO.0285-16.2017en_US
dc.language.isoen_USen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.ispartofeNeuro
dc.subjectAntidepressanten_US
dc.subjectBehavioren_US
dc.subjectDepressionen_US
dc.subjectGABA-NAMen_US
dc.subjectKetamineen_US
dc.subjectγ oscillationen_US
dc.titleA negative allosteric modulator for α5 subunit- containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in miceen_US
dc.typeArticleen_US
dc.identifier.doi10.1523/ENEURO.0285-16.2017
dc.identifier.pmid28275719


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