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.
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.