Repeated us e of 3, 4 methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress: A role of gut microbiota brain axis

3,4Methylenedioxymethamphetamine (MDMA), the most widely used illicit compound worldwide, is the most attractive therapeutic drug for post traumatic stress disorder (PTSD). Recent observational studies of US adults demonstrated that lifetime MDMA use was associated with lower risk of depression. Here, we examined whether repeated administration of MDMA can affect resilience versus susceptibility in mice exposed to chronic social defeat stress (CSDS). CSDS produced splenomegaly, anhedonia-like phenotype, and higher plasma levels of interleukin6 (IL6) in the saline treated mice. In contrast, CSDS did not cause these changes in the MDMA-treated mice. Analysis of gut microbiome found several microbes altered between saline and CSDS group and MDMA and CSDS group. Untargeted metabolomics analysis showed that plasma levels of N epsilon methyl L lysine in the saline and CSDS group were significantly higher than those in the control and MDMA ang CSDS groups. Interestingly, there were positive correlations between plasma IL6 levels and the abundance of several microbes (or plasma N epsilon methyl L lysine) in the three groups. Furthermore, there were also positive correlations between the abundance of several microbes and N epsilon methyl L lysine in the three groups. In conclusion, these data suggest that repeated administration of MDMA might contribute to stress resilience in mice subjected to CSDS through gut microbiota brain axis.