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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
Pałucha-Poniewiera, A.; Rafało-Ulińska, A.; Santocki, M.; Babii, Y.; Kaczorowska, K. 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. Pharmacological Reports 2024, 76, 504–518, doi:10.1007/s43440-024-00588-3.
Pałucha-Poniewiera, A.; Rafało-Ulińska, A.; Santocki, M.; Babii, Y.; Kaczorowska, K. 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. Pharmacological Reports 2024, 76, 504–518, doi:10.1007/s43440-024-00588-3.
Pałucha-Poniewiera, A.; Rafało-Ulińska, A.; Santocki, M.; Babii, Y.; Kaczorowska, K. 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. Pharmacological Reports 2024, 76, 504–518, doi:10.1007/s43440-024-00588-3.
Pałucha-Poniewiera, A.; Rafało-Ulińska, A.; Santocki, M.; Babii, Y.; Kaczorowska, K. 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. Pharmacological Reports 2024, 76, 504–518, doi:10.1007/s43440-024-00588-3.
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.
Medicine and Pharmacology, Pharmacology and Toxicology
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