Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine
Mireia Tarrés-Gatius, Lluis Miquel-Rio, L. Campa, Francesc Artigas, Anna Castañé
Translational Psychiatry December 1, 2020 DOI: 10.1038/s41398-020-01110-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using knockout mice Peer reviewed |
|---|---|
| Population | Wild-type and GluN2C knockout mice of both sexes |
| Intervention | ketamine |
| Topics | Esketamine Ketamine |
| Key findings | GluN2C deletion dramatically reduced ketamine-induced circling behavior in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. |
Abstract
Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 12
- Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments Proceedings of the National Academy of Sciences November 27, 2023
- Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant Frontiers in Pharmacology July 7, 2022
- Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions? American Journal of Psychiatry March 1, 2025
- Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder The World Journal of Biological Psychiatry January 5, 2022
- Involvement of N-methyl-D-aspartate receptor GluN2C/GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles. Journal of Pharmacological Sciences March 1, 2025
and 7 more in the library
Cites 19
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 14 more in the library