Allosteric inhibition of NMDA receptors by low dose ketamine.
Jamie A. Abbott, Han Wen, Beiying Liu, Sheila S Gupta, Gary J Iacobucci, Wenjun Zheng, Gabriela K Popescu
Molecular Psychiatry March 1, 2025 DOI: 10.1038/s41380-024-02729-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Dose | nanomolar concentrations |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressants Mental health Psychopharmacology |
| Citations | 14 |
| Key findings | At nanomolar concentrations, ketamine binds to hydrophobic sites on NMDA receptors distinct from the pore-blocking site, stabilizing pre-open states and preferentially reducing tonic receptor activation while sparing brief synaptic activations. |
Abstract
Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology, structure-based mutagenesis, and molecular and kinetic modeling to investigate the effects of ketamine on NMDA receptors across an extended range of concentrations. We report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, which are distinct from the established pore-blocking site. These interactions stabilize receptors in pre-open states and produce an incomplete, voltage- and pH-dependent reduction in receptor gating. Notably, this allosteric inhibitory mechanism spares brief synaptic-like receptor activations and preferentially reduces currents from receptors activated tonically by ambient levels of neurotransmitters. We propose that the hydrophobic sites we describe here account for clinical effects of ketamine not shared by other NMDA receptor open-channel blockers such as memantine and represent promising targets for developing safe and effective neuroactive therapeutics.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation Normal human subjects | 2003 | Experimental study | n = 7 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression Patients with treatment-resistant bipolar depression | 2012 | Population pharmacokinetic analysis | n = 9 |
Citations in the library
Cited by 7
- Ketamine-From an Anesthetic to a Psychiatric Drug: Mechanisms of Action, Clinical Applications and Potential Risks. Molecules June 30, 2025
- The ketamine chameleon: history, pharmacology, and the contested value of experience. Expert Review of Clinical Pharmacology March 1, 2025
- Inhibition of NMDA receptors and other ion channel types by membrane-associated drugs. Frontiers in Pharmacology 2025
- Modulating tonic NMDA receptor currents: mechanistic insights into ketamine, esketamine, and dextromethorphan for major depressive disorder and implications for the discovery and development of investigational agents. Expert Opinion on Therapeutic Targets January 28, 2026
- Comparative network pharmacology analysis of ketamine and xanomeline in major depressive disorder: Shared and distinct molecular mechanisms. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 20, 2026
and 2 more in the library
Cites 8
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
and 3 more in the library