Pretreatment with MDMA for 14 days blocked anhedonia-like behavior and reduced synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex of mice exposed to chronic restraint stress. Cutting the subdiaphragmatic vagus nerve (vagotomy) blocked these beneficial effects. The gut microbiome showed differences in α-diversity between groups, and specific microbes varied between vehicle- and MDMA-treated stressed mice. Vagotomy prevented increases in three plasma compounds seen in MDMA-treated stressed mice, and two of those compounds correlated positively with several microbes. The data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve may contribute to MDMA-induced stress resilience.
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.
Overexpression of acid sphingomyelinase (ASM) in the forebrain affects addiction-related behaviors differently in male and female mice. In males, forebrain ASM overexpression increased alcohol consumption in a free-choice paradigm and reduced conditioned place preference (CPP) for alcohol and cocaine, but not for amphetamine, ketamine, or high-fat/carbohydrate food. In females, it increased binge-like alcohol drinking while moderate consumption remained unchanged, and enhanced CPP for amphetamine but not other substances. These findings suggest ASM plays a sex-specific role in the reinforcing effects of certain addictive substances, offering potential molecular targets for drug- and sex-specific therapies.