Repeated Administration of 3,4-Methylenedioxymethamphetamine (MDMA) Elevates the Levels of Neuronal Nitric Oxide Synthase in the Nigrostriatal System: Possible Relevance to Neurotoxicity

Previous studies have consistently demonstrated that the amphetamine-related drug 3,4-methylenedioxymethamphetamine (MDMA) induces dopaminergic damage in the mouse brain, and that this effect is most marked in the nigrostriatal system. Moreover, it has been suggested that the overproduction of nitric oxide (NO) may participate in the dopaminergic damage induced by MDMA. To further elucidate this issue, we evaluated the levels of the enzyme nitric oxide synthase (nNOS), which catalyzes the production of NO, in mice treated with regimens of MDMA that induce progressive and persistent neurotoxicity in the dopaminergic nigrostriatal system. Mice received 14, 28, or 36 administrations of MDMA (10 mg/kg i.p.), twice a day/twice a week, and were sacrificed at different time-points after treatment discontinuation. Thereafter, the number of nNOS-positive neurons was quantified by immunohistochemistry in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc). MDMA elevated the numbers of nNOS-positive neurons in the CPu of mice that received 28 or 36 drug administrations. This effect was still detectable at 3 months after treatment discontinuation. Moreover, MDMA elevated the numbers of nNOS-positive neurons in the SNc. However, this effect occurred only in mice that received 28 drug administrations and were sacrificed 3 days after treatment discontinuation. These results are in line with the hypothesis that activation of the NO cascade participates in the toxic effects induced by MDMA in the dopaminergic nigrostriatal system. Moreover, they suggest that activation of the NO cascade induces toxic effects that are more marked in striatal terminals, compared with nigral neurons.