Several amphetamines (AMPHs) including methamphetamine (METH), methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) are popular illicit drugs of abuse. Of great concern is the possibility that the AMPHs may cause long-term damage to central neurons in humans. In the brains of experimental animals, dopaminergic and/or serotonergic neurons are damaged by administration of the AMPHs. The type of monoaminergic neuron damaged depends on both the analog injected as well as the species of animal used. It is not clear why certain analogs exert preferential effects on serotonergic neurons or why there is a species difference in the susceptibility of neurons to damage by the AMPHs. Moreover, the mechanisms by which these compounds produce neurotoxicity are unknown. The AMPHs release both dopamine (DA) and serotonin (5HT) and it has been hypothesized that oxygen-derived products resulting from the oxidation of these monoamines may be the toxic species. We recently found that METH-induced damage to dopaminergic neurons can be prevented by pretreatment of mice with antagonists of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of the glutamate receptor. These findings indicate that excitatory amino acids (EAAs) may be involved in METH-induced dopaminergic toxicity. Our working hypothesis is that the DA released by METH leads to free radical generation and a large release of EAAs which results in a tremendous increase in oxidative stress in dopaminergic nerve terminals. The aims of this research are to gain a greater understanding of how the AMPHs produce toxicity, to study the involvement of EAAs and oxidative stress in their toxicities, to investigate why there is a differential effect of the various analogs on dopaminergic and serotonergic neurons, and to examine why the serotonergic neurons in the rat are so much more susceptible to amphetamine-induced damage than those in the mouse. Biochemical techniques and pharmacological agents will be used to study the actions of the AMPHS. An understanding of the mechanisms by which the AMPHs damage monoaminergic neurons has important implications not only for amphetamine abuse but for disorders of unknown etiology such as Parkinson's Disease, schizophrenia and depression in which there are abnormalities in dopaminergic and serotonergic function.