Grant: Operating Grant

Amphetamines such as ecstasy and speed are used as recreational drugs at parties or raves by college and high school students, and cause severe toxicities. Amphetamine itself and related drugs are widely prescribed to children with attention deficit-hyperactivity disorder. In animal models, amphetamines cause the destruction of particular nerves in the brain, leading to neurodegenerative disorders, and a similar process has been implicated but not proven in humans. Evidence from a number of laboratories including ours suggests that reactive oxygen species (ROS) formed during normal body metabolism may cause neurodegeneration, and that this process is substantially enhanced by drugs like amphetamines that increase ROS formation, which can damage critical components in the brain. We are using several mutant, transgenic and knockout mouse models to elucidate both the neurodegenerative role of ROS and the protective pathways that detoxify ROS or repair the brain damage, with imbalances among these pathways determining individual risk. The lack of such knowledge, together with the growing use of amphetamine abuse and therapeutic use, heighten the clinical importance of such studies, which may facilitate the identification of high-risk individuals and therapeutic strategies to minimize neurodegeneration.