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

Research output: Contribution to journalArticle

Original languageEnglish
JournalNeuropharmacology
Early online date6 Jun 2018
DOIs
DateAccepted/In press - 5 Jun 2018
DateE-pub ahead of print (current) - 6 Jun 2018

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.

    Research areas

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

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0028390818302843?via%3Dihub . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 11 MB, PDF document

    Licence: CC BY-NC-ND

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