Partial mGlu5 Receptor NAM, M-5MPEP, Induces Rapid and Sustained Antidepressant-like Effects in the BDNF-dependent Mechanism and Enhances (R)-Ketamine Action in Mice

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.

Study at a glance

Abstract

Partial negative allosteric modulators (NAM) of the mGlu5 receptor are an excellent alternative to full antagonists and NAMs because they retain some therapeutic effects and, at the same time, have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, M-5MPEP induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in C57BL/6J mice. M-5MPEP caused a rapid, dose-dependent antidepressant-like action in the tail suspension test (TST) 60 min after injection. This effect was antagonized by an AMPA receptor antagonist (NBQX) and a TrkB receptor antagonist (ANA-12) but not by 5HT1A and 5HT2A/2C receptor antagonists. Furthermore, M-5MPEP (30 mg/kg) induced sustained antidepressant-like effects 24 h after the last of four administrations. These effects were revealed in the splash test, designed to measure apathy-like state, and in the TST. Western blot and ELISA analyses indicated the involvement of the TrkB/BDNF pathway in the sustained M-5MPEP effects. Additionally, prolonged effects of M-5MPEP were entirely reversed by the TrkB receptor antagonist ANA-12 in both the splash test and the TST, confirming the critical role of TrkB receptor activation in the sustained antidepressant-like effect of M-5MPEP. Importantly, M-5MPEP enhanced the subthreshold dose of (R)-ketamine in the TST, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression.