(2S,6S)- and (2R,6R)- hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice

HyeWon Heather Kang, Pojeong Park, Muchun Han, Patrick J Tidball, Zuner A Bortolotto, David Lodge, Bong-Kiun Kaang

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of (R,S)-ketamine with the (2S,6S)- and (2R,6R)- isomers of HNK to affect the induction of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in the mouse hippocampus. Following pre-incubation of these compounds we observed a concentration-dependent (1 -10 µM) inhibition of LTP by ketamine and a similar effect of (2S,6S)-HNK. At a concentration of 10 µM (2R,6R)-HNK also inhibited the induction of LTP. These findings raise the possibility that inhibition of NMDAR-mediated synaptic plasticity is a site of action of the HNK metabolites with respect to their rapid and long-lasting antidepressant-like effects.
Original languageEnglish
JournalBrain and Neuroscience Advances
Publication statusAccepted/In press - 20 Aug 2020

Keywords

  • Ketamine
  • Hydroxynorketamine
  • HNK
  • NMDA receptors
  • NMDAR
  • Longterm potentiation
  • LTP
  • Antidepressant

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