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


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.


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; Thomas, Craig; Zarate, Carlos A; Moaddel, Ruin; Traynelis, Stephen F; Pereira, Edna F R; Thompson, Scott M; Albuquerque, Edson X; Gould, Todd D;


  • Animals
  • Antidepressive Agents/ pharmacology
  • Behavior, Animal/ drug effects
  • Excitatory Postsynaptic Potentials/ drug effects
  • Hippocampus/ drug effects
  • Hippocampus/ metabolism
  • Inhibitory Concentration 50
  • Ketamine/ administration & dosage
  • Ketamine/ chemistry
  • Ketamine/ pharmacology
  • Male
  • Mice
  • N-Methylaspartate/ metabolism
  • Protein Subunits/ metabolism
  • Pyramidal Cells/ drug effects
  • Pyramidal Cells/ metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate/ metabolism
  • Xenopus laevis

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