(R)-ketamine induces mGlu5 receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice.
Psychopharmacology May 8, 2025 Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Agata Faron-Górecka et al. 1 citation
In a mouse model of depression, (R)-ketamine altered mGlu5 receptor availability in several brain regions, reversing stress-induced changes in the hippocampus. Adding a partial mGlu5 receptor negative allosteric modulator (M-5MPEP) boosted the effectiveness of a subeffective dose of (R)-ketamine, reducing apathy- and anhedonia-like behaviors. These behavioral improvements were accompanied by changes in hippocampal eEF2 and TrkB protein levels. The findings suggest that weakening mGlu5 receptor function in the hippocampus may contribute to (R)-ketamine's antidepressant-like effects, and combining it with M-5MPEP could enhance its antidepressant activity.