This is a competing renewal application for an Independent Scientist Award (K02) that is intended to enable the applicant to continue engaging in intensive research for an additional five year period. Research in the appplicant's laboratory focuses on substituted amphetamine derivatives (MDMA, methamphetamine, fenfluramine) and their propensity to selectively damage brain serotonin and/or dopamine neurons in animals and, possibly, humans. The long-term goals of this research are to better define the public health consequences of substituted amphetamine exposure and to further elucidate the role of serotonin and dopamine in the central nervous system (CNS), both in health and disease. Additionally, this research seeks to identify the mechanism by which substituted amphetamines damage brain aminergic neurons, as this information may yield insight into the processes underlying neuronal loss in human neurodegenerative disorders. To achieve these broad objectives, over the last five years, the applicant has developed a comprehensive research program that is funded by several grant awards. This research examines the neurotoxic action of MDMA and related drugs at multiple complementary levels. Studies in isolated systems (synaptosomes and cultured cells) and intact animals (rodents) explore mechanisms, identify critical molecular requirements for the expression of substituted amphetamine neurotoxicity, and characterize the short- and long-term responses of serotonin neurons to substituted amphetamine neurotoxicity. Studies in non-human primates seek to more accurately gauge the risk that substituted amphetamines pose to humans. These studies also aid in the development of valid test batteries that can be used in the assessment of recreational substituted amphetamine users. Studies in humans, which include PET imaging studies with neuron-specific ligands, are designed to determine whether users of substituted amphetamines have sustained brain serotonergic or dopaminergic neural injury and, if they have to, to identify possible functional consequences. By decreasing the amount of time required for clinical work, teaching, administration and other departmental duties, renewal of the K02 award will make it possible for the applicant to further his development as a research scientist, and optimize the candidate's chances for making significant new contributions to his field of research, the neurotoxicology of substance abuse.
