This project assesses the role that free radicals might play in the neurotoxic effects associated with amphetamine analogs. Towards that end, we determined the effects of drug of abuse on the dopamine and serotonin systems in adult transgenic mice which overexpress the scavenging enzyme, superoxide dismutase. Oxygen-based radicals are toxic compounds that have been implicated in the causation of a number of neurotoxic and neuropathological events. More recently, because intact dopamine systems are necessary for the manifestation of methamphetamine- induced neurotoxicity, it was suggested that the deleterious effects of these drugs of abuse, including the by-products of their synthesis, might be related to the production of oxygen-based and of other reactive compounds. Several enzymes work in concert to protect the organisms against the ravages of active oxygen species. These include catalase, glutathione peroxidase, and superoxide dismutase. The neurotoxic effects of MPTP were evaluated in a transgenic mouse model which over express the human SOD enzyme. These studies revealed that these animals are protected against the toxic effects of MPTP on the nigrostriatal dopamine system. Administration of methamphetamine (METH) also causes significant depletion in a number of mammalian species. The effects of METH were also tested in the SOD-Tg mice. In Non-Tg mice, acute METH administration caused significant decreases in DA and dihydroxyphenyl acetic acid (DOPAC) in the striata and cortices. In contrast, there were no significant changes in striatal or cortical DA in the SOD-Tg mice. The effects of METH on DOPAC were also attenuated in both structures of these SOD-Tg mice. Chronic administration of METH caused depletion of DA and DOPAC in only the striata of Non-Tg mice. These results suggest that METH-induced neurotoxicity in mice might be secondary to the increased production of superoxide radicals generated during the metabolism of dopamine via monoamine oxidase.
