Mice carrying extra copies of the human superoxide dismutase gene are protected against MDMA-induced damage to brain dopamine neurons. Normal mice showed large drops in striatal dopamine and its metabolite DOPAC one day and two weeks after a single MDMA injection. Mice with one copy of the transgene showed dopamine loss only at one day, while mice with two copies showed no loss at either time point. Three repeated injections caused dopamine loss in normal mice, small losses in one-copy mice, and no loss in two-copy mice. Serotonin levels were unaffected in all groups. The findings indicate that superoxide radicals contribute to MDMA's dopamine toxicity.
Methamphetamine (METH) and MDMA affect dopamine systems differently depending on the presence of P-glycoproteins, which regulate entry into the brain via the blood-brain barrier. In mice lacking the mdr1a gene (knockout), low doses of METH (2.5 mg/kg) caused marked decreases in dopamine and dopamine transporters in the striatum and nucleus accumbens, whereas wild-type mice showed only small changes. Higher METH doses produced similar effects in both strains. Conversely, MDMA caused greater percentage decreases in dopamine transporters in wild-type mice, with the lowest dose (5 mg/kg) significantly reducing transporters in the nucleus accumbens of wild-type but not knockout mice. These findings indicate that P-glycoproteins may facilitate MDMA entry into the brain but interfere with METH entry.