Role of the gut-brain axis via the subdiaphragmatic vagus nerve in stress resilience of 3,4-methylenedioxymethamphetamine in mice exposed to chronic restrain stress.
Youge Qu, Akifumi Eguchi, Li Ma, Xiayun Wan, Chisato Mori, Kenji Hashimoto
Neurobiology of Disease December 1, 2023 DOI: 10.1016/j.nbd.2023.106348 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | MDMA subdiaphragmatic vagotomy |
| Dose | 10 mg/kg/day for 14 days |
| Duration | 14-day intervention |
| Topics | MDMA |
| Keywords | Anhedonia Gut microbiota Resilience Stress Susceptibility |
| Citations | 26 |
| Key findings | Subdiaphragmatic vagotomy blocked MDMA's protective effects against stress-induced anhedonia and molecular changes in mice, indicating that the gut-brain axis via the vagus nerve contributes to MDMA-induced stress resilience. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA use among U.S. adults was associated with a lower risk of depression and suicide thoughts. We recently reported that the gut-brain axis may contribute to MDMA-induced stress resilience in mice. To further explore this, we investigated the effects of subdiaphragmatic vagotomy (SDV) in modulating the stress resilience effects of MDMA in mice subjected to chronic restrain stress (CRS). Pretreatment with MDMA (10 mg/kg/day for 14 days) blocked anhedonia-like behavior and reduced expression of synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex (PFC) of CRS-exposed mice. Interestingly, SDV blocked the beneficial effects of MDMA on these alterations in CRS-exposed mice. Analysis of gut microbiome revealed alterations in four measures of α-diversity between the sham + MDMA + CRS group and the SDV + MDMA + CRS group. Moreover, specific microbes differed between the vehicle + CRS group and the MDMA + CRS group, and further differences in microbial composition were observed among all four groups. Untargeted metabolomics analysis showed that SDV prevented the increase in plasma levels of three compounds [lactic acid, 1-(2-hydroxyethyl)-2,2,6-tetramethyl-4-piperidinol, 8-acetyl-7-hydroxyvumaline] observed in the sham + MDMA + CRS group. Interestingly, positive correlations were found between the plasma levels of two of these compounds and the abundance of several microbes across all groups. In conclusion, our data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve might contribute to the stress resilience of MDMA.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 9
- Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics? European Archives of Psychiatry and Clinical Neuroscience February 27, 2024
- Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis. Neurobiology of Disease September 1, 2024
- Effects of arketamine on depression-like behaviors and demyelination in mice exposed to chronic restrain stress: A role of transforming growth factor-β1. Journal of Affective Disorders December 15, 2024
- Repeated intermittent administration of 3,4-methylenedioxymethamphetamine mitigates demyelination in the brain from cuprizone-treated mice. European Journal of Pharmacology March 15, 2025
- Subdiaphragmatic vagotomy reduces hypothalamic oxytocin expression and blood levels after oral MDMA administration in male rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry March 20, 2025
and 4 more in the library
Cites 25
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology July 19, 2010
- 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry May 1, 2018
- MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine October 1, 2023
- MDMA‐Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta‐Analysis The Journal of Clinical Pharmacology October 28, 2021
and 20 more in the library