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.