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Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5160-5169. doi: 10.1073/pnas.1816071116. Epub 2019 Feb 22.

Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function.

Author information

1
Department of Epidemiology and Public Health, Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201.
2
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
3
Department of Pharmacology, Emory University, Atlanta, GA 30329.
4
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201.
5
Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
6
Pronexus Analytical AB, SE-167 33 Bromma, Sweden.
7
Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224.
8
Section on the Neurobiology and Treatment of Mood Disorders, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892.
9
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892.
10
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201.
11
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
12
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201; gouldlab@me.com.
13
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201.
14
Veterans Affairs Maryland Health Care System, Baltimore, MD 21201.

Abstract

Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine's antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed in Xenopus oocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 µM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.

KEYWORDS:

NMDA receptor; antidepressant; depression; hydroxynorketamine; ketamine

PMID:
30796190
DOI:
10.1073/pnas.1816071116

Conflict of interest statement

Conflict of interest statement: T.D.G. has received research funding from Janssen, Roche, and Allergan Pharmaceuticals, and served as a consultant for FSV7 LLC during the preceding 3 years. The authors declare competing financial interests: T.D.G., P.Z., R.M., P.J.M., C.J.T., and C.A.Z. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. C.A.Z. and R.M. are listed as co-inventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of ketamine metabolites in the treatment of depression and neuropathic pain. R.M., P.J.M., C.J.T., and C.A.Z. have assigned patent rights to the US Government but will share a percentage of any royalties that may be received by the Government. P.Z. and T.D.G. have assigned their patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. S.F.T. received research support from Janssen, is a consultant for Janssen, is a member of the Scientific Advisory Board for Sage Therapeutics, is a co-founder of NeurOp, Inc., and co-inventor on Emory-owned IP. S.J.M. owns stock in NeurOp, Inc., which is developing NMDAR inhibitors for use in treating neurological disease and disorders. All other authors declare no competing interests.

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