The role of mGlu2/3 receptor antagonists in the enhancement of the antidepressant-like effect of ketamine.
Pharmacology, Biochemistry, and Behavior August 1, 2022 DOI: 10.1016/j.pbb.2022.173454 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Animal models of depression |
| Interventions | Ketamine (R)-ketamine mGlu2/3 receptor antagonist |
| Topics | Esketamine Ketamine |
| Key points | Subeffective doses of ketamine or (R)-ketamine coadministered with an mGlu2/3 receptor antagonist induce antidepressant-like effects in animal models without the undesirable effects of higher ketamine doses. |
Abstract
MGlu2/3 receptor antagonists produce antidepressant-like effects in animal models of depression. A number of mechanisms responsible for these actions are convergent to the mechanism of the fast antidepressant-like effect of ketamine. Furthermore, the data indicate that ketamine effect is related to the action of mGlu2 receptors and may be reduced by their agonists. The above facts became the basis for the hypothesis that the antidepressant effect of low doses of ketamine might be enhanced by coadministration of a mGlu2 receptor antagonist. This strategy was aimed not only at enhancing the therapeutic effect of ketamine but also at reducing the risk of undesirable effects by lowering its therapeutic dose. It is known that ketamine, effective in relieving depressive symptoms in patients suffering from treatment-resistant depression (TRD), is burdened with a number of side effects, which may be particularly dangerous in psychiatric patients. Data have confirmed that subeffective doses of ketamine and its enantiomer, (R)-ketamine, coadministered with an mGlu2/3 receptor antagonist, induce antidepressant-like effects in the screening tests and in the chronic-stress-induced model of depression. At the same time, these drug combinations did not cause undesirable effects characteristic of higher doses of ketamine and (S)-ketamine, including those related to psychostimulatory effects. Further research is required to prove whether this strategy will also be effective in depressive patients.
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 5
- Clinical pharmacological innovation in the treatment of depression. Expert Review of Clinical Pharmacology April 1, 2023
- Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice. Pharmacological Reports June 1, 2024
- (R)-ketamine induces mGlu5 receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice. Psychopharmacology May 8, 2025
- Role of group II metabotropic glutamate receptors in ketamine's antidepressant actions. Pharmacology, Biochemistry, and Behavior February 1, 2023
- The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC Pharmaceuticals February 1, 2023
Cites 22
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- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
- Intravenous arketamine for treatment-resistant depression: open-label pilot study European Archives of Psychiatry and Clinical Neuroscience February 20, 2020
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin Neuropsychopharmacology February 24, 2020
and 17 more in the library