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.
A partial negative allosteric modulator of the mGlu5 receptor, M-5MPEP, produced rapid and sustained antidepressant-like effects in C57BL/6J mice. The compound caused a dose-dependent reduction in immobility in the tail suspension test 60 minutes after injection, an effect blocked by an AMPA receptor antagonist (NBQX) and a TrkB receptor antagonist (ANA-12) but not by serotonin receptor antagonists. Sustained effects were observed 24 hours after four administrations, as measured by the splash test and tail suspension test. Western blot and ELISA analyses implicated the TrkB/BDNF pathway. Prolonged effects were fully reversed by ANA-12, confirming TrkB receptor activation's critical role. M-5MPEP also enhanced a subthreshold dose of (R)-ketamine, suggesting convergent mechanisms and potential for treating depression.