Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors.
Elie Adam, Marek Kowalski, Oluwaseun Akeju, Earl K. Miller, Emery N Brown, Michelle M. McCarthy, Nancy Kopell
Proceedings of the National Academy of Sciences May 28, 2024 DOI: 10.1073/pnas.2402732121 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Esketamine Ketamine |
| Keywords | Nmda-receptor antagonism Antidepressant effect Biophysical mechanisms Gamma oscillations Slow-delta oscillations Psychopharmacology Brain-waves Ketamine-research Receptor-biology |
| Citations | 30 |
| Key points | Proposes that NMDA-receptor antagonism by ketamine produces gamma oscillations at high and low doses and slow-delta oscillations at high doses through disinhibition in neuronal circuits and interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition. |
Abstract
Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.
Comparable studies
Other theoretical and historical papers on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. | 2014 | Historical analysis | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Neuroscience and the Near-Death Experience: Roles for the NMSA-PCP receptor, the sigma receptor and the endopsychosins | 1990 | Theoretical or philosophical paper | |
| A unified model of ketamine's dissociative and psychedelic properties. | 2022 | Theoretical or philosophical paper | |
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper |
Citations in the library
Cited by 15
- Anesthetics as Treatments for Depression: Clinical Insights and Underlying Mechanisms. Annual Review of Neuroscience February 19, 2025
- Improvement in pain by using lidocaine combined with esketamine in elderly patients receiving local anaesthesia for percutaneous kyphoplasty: a randomized controlled study. BMC Anesthesiology October 23, 2024
- Connectome harmonic decomposition tracks the presence of disconnected consciousness during ketamine-induced unresponsiveness. British Journal of Anaesthesia April 1, 2025
- Ketamine-Induced Unresponsiveness Shows a Harmonic Shift from Global to Localised Functional Organisation bioRxiv (Cold Spring Harbor Laboratory) June 25, 2024
- General Anesthesia and Discrete Components of Ketamine Neurophysiology. JAMA Psychiatry June 1, 2026
and 10 more in the library
Cites 11
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
and 6 more in the library