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.
Neurobiology of disease – December 01, 2023
Source: PubMed
Summary
Lifetime MDMA use may lower the risk of depression and suicidal thoughts, according to observational studies. In a mouse model, MDMA (10 mg/kg/day for 14 days) effectively blocked anhedonia-like behavior and reduced harmful alterations in the prefrontal cortex among those exposed to chronic stress. However, subdiaphragmatic vagotomy (SDV) negated these benefits. Analysis revealed significant differences in gut microbiota diversity and specific microbial compositions between groups, suggesting the gut-brain axis plays a crucial role in MDMA’s stress resilience effects.
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.