Pharmacological reports : PR
June 1, 2024
Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Michal Santocki et al.
8 citations
A partial negative allosteric modulator of the mGlu5 receptor, M-5MPEP, produced rapid and sustained antidepressant-like effects in mice, similar to the rapid-acting antidepressant ketamine. These effects depended on brain-derived neurotrophic factor (BDNF). M-5MPEP also enhanced the action of (R)-ketamine, suggesting their mechanisms converge. The findings indicate potential for M-5MPEP as a rapid-acting antidepressant with a broader therapeutic window than full antagonists.
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.
Cells
December 11, 2025
Agnieszka Pałucha-Poniewiera
The NMDA receptor antagonist (S)-ketamine produces rapid and lasting antidepressant effects in patients resistant to traditional treatments, validating the glutamatergic hypothesis of depression proposed over 20 years ago. However, (S)-ketamine also causes side effects that limit its safety. Preclinical studies suggest that low doses of mGlu2 and mGlu5 receptor antagonists can enhance ketamine's therapeutic effects while reducing its side effects. This review examines the synergistic interaction between ketamine and these glutamatergic modulators, the underlying mechanisms, and the role of mGlu2 and mGlu5 receptors in ketamine's antidepressant action.
The International Journal of Neuropsychopharmacology
August 1, 2025
Yana Babii, C. Barbara, Dorota Bederska‐łojewska et al.
Hallucinogens from different classes, such as scopolamine and psilocybin, show rapid antidepressant effects that are enhanced by blocking group II metabotropic glutamate (mGlu2/3) receptors. In mice, scopolamine reversed depressive-like behaviors induced by chronic mild stress, and a selective M1 muscarinic antagonist produced dose-dependent antidepressant effects potentiated by an mGlu2 receptor negative allosteric modulator. Scopolamine increased extracellular dopamine, serotonin, and glutamate in the frontal cortex, while the mGlu2 modulator had opposite effects on glutamate. A low dose of the mGlu2/3 antagonist LY341495 boosted the antidepressant effect of low-dose psilocybin in the tail suspension test, with rapid onset and long duration, while also reducing hallucinogenic-like head twitch responses. Combined targeting of these systems may allow lower doses and fewer side effects while maintaining antidepressant efficacy.