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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 11; pp. 5160 - 5169
• Main Authors: Lumsden, Eric W., Troppoli, Timothy A., Myers, Scott J., Zanos, Panos, Aracava, Yasco, Kehr, Jan, Lovett, Jacqueline, Kim, Sukhan, Wang, Fu-Hua, Schmidt, Staffan, Jenne, Carleigh E., Yuan, Peixiong, Morris, Patrick J., Thomas, Craig J., Zarate, Carlos A., Moaddel, Ruin, Traynelis, Stephen F., Pereira, Edna F. R., Thompson, Scott M., Albuquerque, Edson X., Gould, Todd D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12-03-2019
• Series: PNAS Plus
• Subjects: Animals; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Biological Sciences; Brain slice preparation; Excitatory postsynaptic potentials; Excitatory Postsynaptic Potentials - drug effects; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Inhibition; Inhibitory Concentration 50; Ketamine; Ketamine - administration & dosage; Ketamine - chemistry; Ketamine - pharmacology; Lethality; Male; Medicin och hälsovetenskap; Mice; N-Methyl-D-aspartic acid receptors; N-Methylaspartate - metabolism; Oocytes; PNAS Plus; Protein Subunits - metabolism; Pyramidal cells; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Rats; Receptors; Receptors, N-Methyl-D-Aspartate - metabolism; Stereoisomers; Stereoselectivity; Xenopus laevis; hydroxynorketamine; depression; NMDA receptor; ketamine; antidepressant
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1816071116

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.