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

• Type of Material: Article
• Authors: Eric W. Lumsden, University of Maryland; Timothy A. Troppoli, University of Maryland; Scott J. Myers, Emory University; Panos Zanos, University of Maryland; Yasco Aracava, University of Maryland; Jan Kehr, Karolinska Institutet; Jacqueline Lovett, National Institutes of Health; Sukhan Kim, Emory University; Fu-Ha Wang, Karolinska Institutet; Staffan Schmidt, Karolinska Institutet; Carleigh E. Jenne, University of Maryland; Peixiong Yuan, National Institutes of Health; Patrick J. Morris, National Institutes of Health; Craig J. Thomas, National Institutes of Health; Carlos A. Zarate, National Institutes of Health; Ruin Moaddel, National Institutes of Health; Stephen Traynelis, Emory University; Edna F. R. Pereira, University of Maryland; Scott M. Thompson, University of Maryland; Edson X. Albuquerque, University of Maryland; Todd D. Gould, University of Maryland
• Language: English
• Date: 2019-03-12
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1816071116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 116
• Issue: 11
• Start Page: 5160
• End Page: 5169
• Grant/Funding Information: R.M., C.A.Z., and C.J.T. are supported by the NIH Intramural Research Program.; This work was supported by NIH Grant R01MH107615, Veterans Affairs Merit Award 1I01BX004062, and a Harrington Discovery Institute Scholar-Innovator grant (to T.D.G.), NIH Grant R01MH086828 and the Kahlert Foundation (to S.M.T.), and NIH Grant R01NS065371 (to S.F.T.), and was also supported through a NIH Bench-to-Bedside award (to T.D.G. and C.A.Z.).
• Keywords: ketamine; SUBUNIT; PLASMA; TRIAL; antidepressant; NMDA receptor; COMPLEX; D-ASPARTATE ANTAGONIST; MK-801; Multidisciplinary Sciences; Science & Technology; depression; Science & Technology - Other Topics; INFUSION; RAT; PHARMACOLOGY; hydroxynorketamine
• Research Categories: Psychology, General; Biology, Neuroscience; Health Sciences, Pharmacology

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) NMDARmediated 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 ED 50 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.