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.
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.