Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): Evidence from using CuZn‐superoxide dismutase transgenic mice

The subacute and long‐term biochemical effects of methylenedioxymeth‐amphetamine (MDMA) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper‐zinc (CuZn) superoxide dismutase (SOD) gene. Non‐transgenic (Non‐Tg) mice showed significant decreased in striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels both at 24 h and at 2 weeks after a single injection of MDMA (50 mg/kg). Heterozygous SOD‐Tg mice showed DA depletion only at the 24 h time point. In contrast, homozygous SOD‐Tg mice show no DA or DOPAC depletion at either the 24 h or at the 2 week time points. Moreover, three injections of MDMA (50 mg/kg) given 24 h apart also caused marked reduction of striatal DA and DOPAC in Non‐Tg mice when these substances were measured 2 weeks after the last MDMA injection. That injection schedule also caused small decreases in DA levels in the heterozygous animals but no changes in the homozygous mice; DOPAC levels were not affected in the heterozygous nor in the homozygous SOD‐Tg mice. Furthermore, the multiple injection schedule caused significant decreases in DA and DOPAC in female Non‐Tg mice but not in the two strains of transgenic mice. Neither the single dose nor the multiple dose schedule of MDMA injections affected striatal serotonin (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIM)levels in any of the three strains of mice. These results support previous observations that MDMA‐induced biochemical effects are observed in the DA systems of mice, whereas these effects are seen in the 5‐HT systems of rats. The present observations also document for the first time a role for the production of superoxide radicals in these effects of MDMA. These mice are an important tool for dissecting pathways involved in drug‐induced neurotoxicity. © 1995 Wiley‐Liss, Inc.