Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms
Chrislean Jun Botanas, June Bryan De la Peña, Raly James Perez Custodio, Irene Joy Dela Peña, Mikyung Kim, Taeseon Woo, H. Kim, Hye In Kim, Min Chang Cho, Yong Sup Lee, J. Cheong
Neuropharmacology November 1, 2017 DOI: 10.1016/j.neuropharm.2017.08.038 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Methoxetamine (MXE) |
| Dose | 2.5, 5, or 10 mg/kg |
| Topics | Serotonin |
| Key findings | MXE produced antidepressant effects in mice at 30 minutes and 24 hours after treatment, and these effects were blocked by NBQX and ketanserin, suggesting mediation by glutamatergic and serotonergic systems. MXE also altered hippocampal gene expression related to these systems. |
Abstract
Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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- Rodent ketamine depression-related research: Finding patterns in a literature of variability Behavioural Brain Research August 13, 2019
- Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents Journal of Psychopharmacology July 10, 2020
- R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine. Neuropharmacology August 1, 2021
- Dorsolateral Prefrontal Cortex Impairment in Methoxetamine-Induced Psychosis: An 18F-FDG PET/CT Case Study Journal of Psychoactive Drugs February 9, 2019
- Serotonin 2C receptors are also important in head-twitch responses in male mice. Psychopharmacology July 1, 2025
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Cites 11
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and 6 more in the library