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Zanos et al. reply

Nature volume 546, pages E4–E5 (2017)Cite this article

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Replying to K. Suzuki et al. Nature 546, http://dx.doi.org/10.1038/nature22084 (2017)

In the accompanying Comment1, Suzuki et al. confirmed our previous findings2 that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) does not functionally inhibit the NMDAR at concentrations relevant to its antidepressant actions recently reported in mice (that is, approximately 10 μM). We reported that 10 μM (2R,6R)-HNK, which equates to the maximum concentration of brain exposure (10.69 μM (ref. 2)) after intraperitoneal administration of a 10 mg kg−1 antidepressant dose of (2R,6R)-HNK in mice, robustly potentiated excitatory postsynaptic potentials in hippocampal slices without functionally inhibiting the NMDAR2, as Suzuki et al. now confirm. Unless NMDAR inhibition is observed at 10 μM (2R,6R)-HNK, it is probably not of major relevance to the antidepressant actions of (2R,6R)-HNK. Notably, (2R,6R)-HNK administration also resulted in significant antidepressant actions at the dose of 5 mg kg−1 in mice, which would produce even lower concentrations of the metabolite in the brain than 10 μM (ref. 2). Furthermore, our field-potential electrophysiology experiments were conducted in the presence of the NMDAR antagonist AP5 (80 μM), demonstrating that the AMPAR-mediated synaptic potentiation we observed is independent of any capacity of (2R,6R)-HNK to inhibit the NMDAR.

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Authors and Affiliations

  1. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Panos Zanos, Polymnia Georgiou, Greg I. Elmer, Heather J. Pribut, Scott M. Thompson & Todd D. Gould

  2. Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, 21224, Maryland, USA

    Ruin Moaddel, Nagendra S. Singh & Katina S. S. Dossou

  3. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, 20892, Maryland, USA

    Patrick J. Morris, Yuhong Fang & Craig J. Thomas

  4. Department of Physiology, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Jonathan Fischell & Scott M. Thompson

  5. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Greg I. Elmer, Edson X. Albuquerque & Todd D. Gould

  6. Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, 21228, Maryland, USA

    Greg I. Elmer & Cheryl L. Mayo

  7. Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Manickavasagom Alkondon & Edson X. Albuquerque

  8. Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, 20814, Maryland, USA

    Peixiong Yuan & Carlos A. Zarate

  9. Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, NIMH Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, Chapel Hill, North, 27516, Carolina, USA

    Xi-Ping Huang

  10. Department of Medicine, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Edson X. Albuquerque

  11. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Todd D. Gould

Authors
  1. Panos Zanos
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Correspondence to Todd D. Gould.

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Zanos, P., Moaddel, R., Morris, P. et al. Zanos et al. reply. Nature 546, E4–E5 (2017). https://doi.org/10.1038/nature22085

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