Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity

Rachel Ingram, HyeWon Heather Kang, Stafford Lightman, David Jane, Zuner Bortolotto, Graham Collingridge, David Lodge, Arturas Volianskis

Research output: Contribution to journalArticle (Academic Journal)

9 Citations (Scopus)
226 Downloads (Pure)

Abstract

Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 μM) IC50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC50 value ∼ 15 μM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory.
Original languageEnglish
JournalNeuropharmacology
Early online date6 Jun 2018
DOIs
Publication statusE-pub ahead of print - 6 Jun 2018

Keywords

  • Psychedelics
  • Ketamine
  • Phencyclidine
  • PCP
  • NMDA receptors
  • GluN2D subunit
  • Short-term potentiation
  • STP
  • Long-term potentiation
  • LTP;
  • Working Memory
  • Memory

Fingerprint Dive into the research topics of 'Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity'. Together they form a unique fingerprint.

  • Student Theses

    Characterization of dissociative anesthetics acting at the NMDA receptor site

    Author: Kang, H. H., 19 Mar 2019

    Supervisor: Lightman, S. (Supervisor) & Collingridge, G. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

    File

    Cite this