title: A 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 Mice.
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.
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine , Baltimore, MD 21201.
authors.forename: Panos
authors.identifier: 0000-0002-1968-8648
authors.initials: P
authors.lastname: Zanos
authors.affiliation: Department of Physiology, University of Maryland School of Medicine , Baltimore, MD 21201.
authors.forename: Mackenzie E
authors.initials: ME
authors.lastname: Nelson
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201; Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Jaclyn N
authors.identifier: 0000-0002-9600-2830
authors.initials: JN
authors.lastname: Highland
authors.affiliation: Program in Neuroscience, University of Maryland School of Medicine , Baltimore, MD 21201.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Krimmel
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine , Baltimore, MD 21201.
authors.forename: Polymnia
authors.initials: P
authors.lastname: Georgiou
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201; Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201; Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201; Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Thompson
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D065818:Gamma Rhythm / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology*; D007649:Ketamine / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D065808:Prepulse Inhibition / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D018683:Excitatory Amino Acid Agents; C496250:Gabra5 protein, mouse; D007555:Isoxazoles; C494554:MRK 016; D011810:Quinoxalines; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D014227:Triazines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007649:Ketamine
keywords: GABA-NAM; antidepressant; behavior; depression; ketamine; γ oscillation