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.
Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Michal Santocki, Yana Babii, Katarzyna Kaczorowska
Pharmacological reports : PR June 1, 2024 DOI: 10.1007/s43440-024-00588-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | M-5MPEP (R)-ketamine |
| Duration | Acute and 24 hours after four intraperitoneal administrations |
| Topics | Esketamine Ketamine |
| Keywords | Bdnf M-5mpep Raad Trkb receptor Mglu5 receptor Depression treatment Antidepressants Neuroscience research Drug development Brain chemistry |
| Citations | 8 |
| Key points | Partial mGlu5 NAM M-5MPEP induced rapid and sustained antidepressant-like effects in mice via a BDNF-dependent mechanism and enhanced (R)-ketamine action. |
Abstract
Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24 h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.