ALBERT

Description: 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 (alpha-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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanos, Panos -- Moaddel, Ruin -- Morris, Patrick J -- Georgiou, Polymnia -- Fischell, Jonathan -- Elmer, Greg I -- Alkondon, Manickavasagom -- Yuan, Peixiong -- Pribut, Heather J -- Singh, Nagendra S -- Dossou, Katina S S -- Fang, Yuhong -- Huang, Xi-Ping -- Mayo, Cheryl L -- Wainer, Irving W -- Albuquerque, Edson X -- Thompson, Scott M -- Thomas, Craig J -- Zarate, Carlos A Jr -- Gould, Todd D -- HHSN-271-2008-025C/PHS HHS/ -- HHSN271201000008I/PHS HHS/ -- MH086828/MH/NIMH NIH HHS/ -- MH099345/MH/NIMH NIH HHS/ -- MH107615/MH/NIMH NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2016 May 4;533(7604):481-6. doi: 10.1038/nature17998.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. ; Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. ; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, USA. ; Department of Physiology, 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. ; Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. ; Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 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. ; Department of Medicine, 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27144355" target="_blank"〉PubMed〈/a〉