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 language | English |
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Pages (from-to) | 30-40 |
Journal | Neuropharmacology |
Volume | 142 |
Early online date | 6 Jun 2018 |
DOIs | |
Publication status | E-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
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Characterization of dissociative anesthetics acting at the NMDA receptor site
Kang, H. H. (Author), Lightman, S. (Supervisor) & Collingridge, G. (Supervisor), 19 Mar 2019Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)
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