Free radicals and the pathobiology of brain dopamine systems

Oxygen is an essential element for normal life. However, reactive oxygen species (ROS) can also participate in deleterious reactions that can affect lipid, protein, and nucleic acid. Normal physiological function thus depends on a balance between these ROS and the scavenging systems that aerobic organisms have developed over millennia. Tilting of that balance towards a pro-oxidant state might result from both endogenous and exogenous causes. In the present paper, we elaborate on the thesis that the neurodegenerative effects of two drugs, namely methamphetamine (METH, ICE) and methylenedioxymethamphetamine (MDMA, Ecstasy) are due to ROS overproduction in monoaminergic systems in the brain. We also discuss the role of oxygen-based species in 6-hydroxydopamine (6-OHDA)-induced nigrostriatal dopaminergic degeneration and in Parkinson's disease. Studies are underway to identify specific cellular and molecular mechanisms that are regulated by oxygen species. These studies promise to further clarify the role of oxidative stress in neurodegeneration and in plastic changes that occur during the administration of addictive agents that affect the brain.