Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity.
Rachael Ingram, Heather Kang, Stafford Lightman, David E Jane, Zuner A. Bortolotto, Graham L. Collingridge, David Lodge, Arturas Volianskis
Neuropharmacology November 2018 DOI: 10.1016/j.neuropharm.2018.06.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | Ketamine UBP145 |
| Topics | Ketamine Esketamine Neuroplasticity |
| Keywords | Glun2d subunit Ltp Long-term potentiation Nmda receptors Pcp Phencyclidine Psychedelics Stp Short-term potentiation Working memory |
| Key points | Ketamine inhibits short-term potentiation (STP) with a double sigmoidal dose-response curve (IC50 values of 40 nM and 5.6 μM) and long-term potentiation (LTP) with a single sigmoidal curve (IC50 approximately 15 μM). The GluN2D-preferring antagonist UBP145 shows a similar profile. The authors propose that ketamine's psychedelic effects may involve inhibition of STP and potentially associated working memory processes. |
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. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
Comparable studies
Other theoretical and historical papers on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential? | 2021 | Theoretical or philosophical paper | |
| A complex systems perspective on psychedelic brain action. | 2023 | Theoretical or philosophical paper | |
| Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy | 2021 | Theoretical or philosophical paper | |
| Therapeutic mechanisms of psychedelics and entactogens. | 2023 | Theoretical or philosophical paper |
Citations in the library
Cited by 12
- Global Street Food: la cocina de la calle Diseño interior 2009
- Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior International Journal of Molecular Sciences June 16, 2022
- Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Molecular Brain June 16, 2020
- Psychedelics and Psychedelic-Assisted Psychotherapy FOCUS: The Journal of Lifelong Learning in Psychiatry 2021
- Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia International Journal of Molecular Sciences July 23, 2023
and 7 more in the library
Cites 21
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- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
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and 16 more in the library