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

NEUROPHARMACOLOGY

卷:142

Review

Ingram, Rachael¹  Kang, Heather^2,3,4,5  Lightman, Stafford²  Jane, David E.³  Bortolotto, Zuner A.³  Collingridge, Graham L.^3,4,5  Lodge, David³  Volianskis, Arturas^1,2 

[1] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Neurosci & Trauma, London, England

[2] Univ Bristol, Sch Clin Sci, Bristol, Avon, England

[3] Univ Bristol, Sch Physiol Pharmacol & Neurosci, Ctr Synapt Plast, Bristol, Avon, England

[4] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[5] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

关键词: Psychedelics;    Ketamine;    Phencyclidine;    PCP;    NMDA receptors;    GluN2D subunit;    Short-term potentiation;    STP;    Long-term potentiation;    LTP;    Memory;    Working memory;   

DOI  :  10.1016/j.neuropharm.2018.06.008

来源: Elsevier

【 摘 要 】

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 mu M) IC50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC50 value similar to 15 mu M). A GIuN2D-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. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. (C) 2018 Published by Elsevier Ltd.

【 授权许可】

Free