title: NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
abstract: Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Zanos
authors.affiliation: Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morris
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Polymnia
authors.initials: P
authors.lastname: Georgiou
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fischell
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA.
authors.forename: Greg I
authors.initials: GI
authors.lastname: Elmer
authors.affiliation: Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Manickavasagom
authors.initials: M
authors.lastname: Alkondon
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peixiong
authors.initials: P
authors.lastname: Yuan
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Pribut
authors.affiliation: Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Singh
authors.affiliation: Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Katina S S
authors.initials: KS
authors.lastname: Dossou
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Fang
authors.affiliation: NIMH Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27516, USA.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Mayo
authors.affiliation: Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Edson X
authors.initials: EX
authors.lastname: Albuquerque
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Thompson
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D007649:Ketamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; C050654:6-hydroxynorketamine