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NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Author

Listed:
  • Panos Zanos

    (University of Maryland School of Medicine)

  • Ruin Moaddel

    (Biomedical Research Center, National Institute on Aging, National Institutes of Health)

  • Patrick J. Morris

    (National Center for Advancing Translational Sciences, National Institutes of Health)

  • Polymnia Georgiou

    (University of Maryland School of Medicine)

  • Jonathan Fischell

    (University of Maryland School of Medicine)

  • Greg I. Elmer

    (University of Maryland School of Medicine
    University of Maryland School of Medicine
    Maryland Psychiatric Research Center, University of Maryland School of Medicine)

  • Manickavasagom Alkondon

    (University of Maryland School of Medicine)

  • Peixiong Yuan

    (Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health)

  • Heather J. Pribut

    (University of Maryland School of Medicine)

  • Nagendra S. Singh

    (Biomedical Research Center, National Institute on Aging, National Institutes of Health)

  • Katina S. S. Dossou

    (Biomedical Research Center, National Institute on Aging, National Institutes of Health)

  • Yuhong Fang

    (National Center for Advancing Translational Sciences, National Institutes of Health)

  • Xi-Ping Huang

    (NIMH Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School)

  • Cheryl L. Mayo

    (Maryland Psychiatric Research Center, University of Maryland School of Medicine)

  • Irving W. Wainer

    (Biomedical Research Center, National Institute on Aging, National Institutes of Health
    † Present address: Mitchell Woods Pharmaceuticals, Shelton, Connecticut 06484, USA.)

  • Edson X. Albuquerque

    (University of Maryland School of Medicine
    University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Scott M. Thompson

    (University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Craig J. Thomas

    (National Center for Advancing Translational Sciences, National Institutes of Health)

  • Carlos A. Zarate Jr

    (Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health)

  • Todd D. Gould

    (University of Maryland School of Medicine
    University of Maryland School of Medicine
    University of Maryland School of Medicine)

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.

Suggested Citation

  • Panos Zanos & Ruin Moaddel & Patrick J. Morris & Polymnia Georgiou & Jonathan Fischell & Greg I. Elmer & Manickavasagom Alkondon & Peixiong Yuan & Heather J. Pribut & Nagendra S. Singh & Katina S. S. , 2016. "NMDAR inhibition-independent antidepressant actions of ketamine metabolites," Nature, Nature, vol. 533(7604), pages 481-486, May.
  • Handle: RePEc:nat:nature:v:533:y:2016:i:7604:d:10.1038_nature17998
    DOI: 10.1038/nature17998
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    Citations

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    Cited by:

    1. Sharvari Shivanekar & Priya Gopalan & Anthony Pizon & Crystal Spotts & Nicolas Cruz & Michael Lightfoot & Rebecca Rohac & Andrew Baumeister & Angela Griffo & Benjamin Panny & Shelly Kucherer & Alex Is, 2022. "A Pilot Study of Ketamine Infusion after Suicide Attempt: New Frontiers in Treating Acute Suicidality in a Real-World Medical Setting," IJERPH, MDPI, vol. 19(21), pages 1-15, October.
    2. Radhika Rawat & Elif Tunc-Ozcan & Tammy L. McGuire & Chian-Yu Peng & John A. Kessler, 2022. "Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Jackie Zhu & Elisa Hawkins & Kristin Phillips & Laxmikant S. Deshpande, 2020. "Assessment of Ketamine and its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness," IJERPH, MDPI, vol. 17(13), pages 1-16, June.
    4. Francis Kei Masuda & Emily A. Aery Jones & Yanjun Sun & Lisa M. Giocomo, 2023. "Ketamine evoked disruption of entorhinal and hippocampal spatial maps," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Tommaso Ianni & Sedona N. Ewbank & Marjorie R. Levinstein & Matine M. Azadian & Reece C. Budinich & Michael Michaelides & Raag D. Airan, 2024. "Sex dependence of opioid-mediated responses to subanesthetic ketamine in rats," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Fangyun Tian & Laura D. Lewis & David W. Zhou & Gustavo A. Balanza & Angelique C. Paulk & Rina Zelmann & Noam Peled & Daniel Soper & Laura A. Santa Cruz Mercado & Robert A. Peterfreund & Linda S. Agli, 2023. "Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Shi-Ge Xue & Jin-Gang He & Ling-Li Lu & Shi-Jie Song & Mei-Mei Chen & Fang Wang & Jian-Guo Chen, 2023. "Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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