The role of mGluR5 on the therapeutic effects of ketamine in Wistar rats.
Dilan Gokalp, Gunes Unal
Psychopharmacology July 1, 2024 DOI: 10.1007/s00213-024-06571-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Adult male Wistar rats |
| Intervention | ketamine |
| Dose | 10 mg/kg ketamine, 1 mg/kg ketamine |
| Topics | Anxiety Ketamine Esketamine |
| Keywords | Behavioral despair Cdppb Epm Fst Fear Mtep Oft Mglur5 Ketamine antidepressants Neuroscience research Behavioral pharmacology Depression treatment |
| Key findings | Suppressed mGluR5 activity is required for ketamine's antidepressant effects, and mGluR5 antagonism enhances the antidepressant effectiveness of low-dose ketamine but eliminates its anxiolytic effects. |
Abstract
Ketamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has a complex mechanism of action that involve alterations in other glutamate receptors. The metabotropic glutamate receptor 5 (mGluR5) has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown. We investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats. Two sets of experiments were conducted. We first utilized the positive allosteric modulator CDPPB to investigate how acute mGluR5 activation regulates the therapeutic effects of ketamine (10 mg/kg). We then tested the synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning. Enhancing mGluR5 activity via CDPPB occluded the antidepressant effect of ketamine without changing locomotor activity. Furthermore, concomitant administration of MTEP and ketamine exhibited a robust synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine. These findings suggest that suppressed mGluR5 activity is required for the antidepressant effects of ketamine. Consequently, the antagonism of mGluR5 enhances the antidepressant effectiveness of low dose ketamine, but eliminates its anxiolytic effects.
Comparable studies
Other preclinical and animal studies on ketamine for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Wistar rats | 2018 | Experimental study | n = 40 |
| Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One? Rodents | 2021 | Review | |
| Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents | 2024 | Review | |
| Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration Arc-CreERT2 × CAG-Sun1/sfGFP mice | 2020 | Experimental study |
Citations in the library
Cited by 10
- Environmental enrichment enhances the antidepressant effect of ketamine and ameliorates spatial memory deficits in adult rats. Pharmacology, Biochemistry, and Behavior July 1, 2024
- Effects of ketamine on fear memory extinction: a review of preclinical literature. Frontiers in Neuroscience 2025
- Estrogen receptor alpha (ERα) partially modulates ketamine's sustained anxiolytic effects without altering its antidepressant properties in female rats. Psychoneuroendocrinology July 1, 2025
- Ketamine differentially affects implicit and explicit memory processes in rats. Psychopharmacology June 1, 2025
- Esketamine-mediated alleviation of electroconvulsive shock-induced memory impairment is associated with the regulation of mGluR5 in depressive-like rats. Pharmacology, Biochemistry, and Behavior March 1, 2025
and 5 more in the library
Cites 25
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- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- ( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions Proceedings of the National Academy of Sciences March 13, 2019
and 20 more in the library