Depression-like effects induced by chronic unpredictable mild stress in mice are rapidly reversed by a partial negative allosteric modulator of mGlu receptor, M-5MPEP.

Rationale: Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.

Objectives: The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.

Methods: Chronic unpredictable mild stress (CUMS) was used as an animal model of depression. The effects of single and four-day administration of M-5MPEP on CUMS-induced animal behaviors reflecting anhedonia, apathy, and helplessness were studied. Western blot was applied to measure the levels of proteins potentially involved in a rapid antidepressant effect, including mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), tropomyosin receptor kinase B (TrkB), and serotonin transporter (SERT), both in the hippocampus and the prefrontal cortex (PFC). Furthermore, excitatory synaptic transmission and long-term potentiation (LTP) were measured in the medial PFC (mPFC).

Results: We showed that M-5MPEP administration for four consecutive days abolished CUMS-induced apathy- and anhedonia-like symptoms in a mouse model of depression. We also found that these effects were accompanied by changes in hippocampal TrkB levels and mTOR and eEF2 levels in the PFC. Using electrophysiological techniques, we showed that the four-day M-5MPEP treatment reversed chronic stress-induced increases in excitatory synaptic potential and CUMS-impaired LTP in the mPFC.

Conclusions: Partial mGlu receptor NAM, M-5MPEP, appears to be a potentially effective new RAAD and deserves further study.