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 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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 4
- (R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders. International Journal of Molecular Sciences June 20, 2024
- (R)-ketamine induces mGlu5 receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice. Psychopharmacology May 8, 2025
- Molecular signature underlying (R)-ketamine rapid antidepressant response on anhedonic-like behavior induced by sustained exposure to stress. Pharmacology, Biochemistry, and Behavior December 1, 2024
- Modulation of Metabotropic Glutamate Receptors as a Strategy to Improve the Efficacy and Safety of Ketamine as an Antidepressant Cells December 11, 2025
Cites 17
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
- Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model Translational Psychiatry February 23, 2016
and 12 more in the library