Repeated exposure to MDMA (ecstasy) causes long-lasting changes in the brain, particularly accumulation of the protein ΔFosB in several regions. In male rats, MDMA self-administration significantly increased ΔFosB in the nucleus accumbens core, parts of the caudate-putamen, several cortical areas, and the amygdala, but not in other striatal regions. Pretreatment with MDMA enhanced the drug's locomotor-activating effect only when injected into the nucleus accumbens or medial caudate-putamen, matching the ΔFosB pattern. These findings resemble those seen with other addictive drugs, suggesting common neuroplastic changes underlying addiction.
Combining behavioral models with metabolomics can help identify which metabolites are most relevant to substance use disorders. In a preclinical experiment, untargeted metabolomics was performed on 336 microdialysis samples from the medial striatum of 21 male Sprague-Dawley rats during an MDMA-induced behavioral sensitization study. Orthogonal partial least squares analysis, using behavioral data as the Y variable and relative concentrations of 737 detected features as X variables, revealed that MDMA and its derivatives, serotonin, and several dopamine/norepinephrine metabolites were the strongest predictors of acute MDMA-produced behavior. Repeated MDMA exposure significantly altered MDMA metabolism, which may contribute to increased abuse liability with repeated use. Including behavioral data guides metabolomics analysis and enhances relevance to the phenotype of interest.