Figure 6.

A hypothetical model of MDMA-induced dopaminergic toxicity in mice. The inhibition of mitochondrial complex I activity after systemic administration of MDMA promotes the generation of superoxide radicals (O₂^•−), which could lead to the formation of peroxynitrite (ONOO^-), in the presence of NO, or to H₂O₂ by means of superoxide dismutase (SOD). The [4Fe-4S]²⁺ cluster of aconitase could then be inactivated by O₂^•−, peroxynitrite or H₂O₂ leading to the generation of Fe²⁺, which, together with H₂O₂, may increase the formation of hydroxyl radicals (OH^•) by the Fenton reaction. Glutathione (GSH) is involved both as a non-enzymic, free radical scavenger for ROS and/or peroxynitrite and enzymically to inactivate H₂O₂. In summary, inhibition of mitochondrial complex I activity could be a plausible source of free radicals responsible for oxidative damage to dopamine neurons caused by MDMA in mice. Further studies are needed, however, to resolve which is/are the specific compound(s) responsible for such effects. GPx, gluthathione peroxidase; GR, glutathione reductase; MDMA, 3,4-methylenedioxymethamphetamine; ROS, reactive oxygen species.