Studies of Substituted Amphetamine Neurotoxicity

描述(由申请人提供)： 本修订后的高级科学家奖(K05)申请书旨在使申请者能够在未来五年继续从事药物滥用研究。申请人实验室的研究重点是取代的苯丙胺衍生物(MDMA、甲基苯丙胺)及其选择性损害动物和可能还有人类的大脑5-羟色胺和/或多巴胺神经元的倾向。这项研究的长期目标是更好地确定替代苯丙胺暴露在人类中的风险和后果，并进一步阐明5-羟色胺和多巴胺在中枢神经系统(CNS)中的作用，无论是健康还是疾病。此外，这项研究试图确定替代苯丙胺损伤脑胺能神经元的机制，因为这些信息可能有助于深入了解人类神经退行性疾病中潜在的神经元丢失过程。 为了实现这些目标，人们使用了各种方法。在分离系统(基因芯片、突触体和培养细胞)和完整动物(啮齿动物)中的研究探索了替代苯丙胺神经毒性的机制，确定了表达神经毒性的关键分子要求，并表征了5-羟色胺和多巴胺神经元对替代苯丙胺神经毒性的短期和长期反应。对非人类灵长类动物的研究试图更准确地评估替代苯丙胺对人类构成的风险，并开发和验证检测替代苯丙胺对人类神经毒性后果的方法。在人类身上进行的研究，包括分子PET成像、药理学挑战、神经精神病学评估、认知测试和多导睡眠图评估，旨在确定使用替代苯丙胺的人类是否会出现神经毒性，如果会，则会产生功能后果。 通过减少临床工作、教学、行政和其他部门职责所需的时间，这项K05奖项将使申请者能够优化研究生产率，继续在其实验室培训初级教员和研究员，并参与旨在教育公众有关替代苯丙胺的神经毒性潜力的国内和国际论坛。

DESCRIPTION (provided by applicant): This revised application for a Senior Scientist Award (K05) is submitted to enable the applicant to continue engaging in drug abuse research for the next five years. Research in the applicant's laboratory focuses on substituted amphetamine derivatives (MDMA, methamphetamine) 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 risks and consequences of substituted amphetamine exposure in humans, and to further elucidate the role of serotonin and dopamine in the central nervous system (CNS), both in health and disease. In addition, 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 conditions. A variety of methods are used to achieve these goals. Studies in isolated systems (gene microarrays, synaptosomes and cultured cells) and intact animals (rodents) explore mechanisms of substituted amphetamine neurotoxicity, identify critical molecular requirements for the expression of neurotoxicity, and characterize the short- and long-term responses of serotonin and dopamine neurons to substituted amphetamine neurotoxicity. Studies in nonhuman primates seek to more accurately gauge the risk that substituted amphetamines pose to humans and to develop and validate methods for detecting the consequences of substituted amphetamine neurotoxicity in humans. Studies in humans, which include molecular PET imaging, pharmacologic challenges, neuropsychiatric evaluations, cognitive testing and polysomnographic evaluations, are designed to determine whether humans who use substituted amphetamines develop neurotoxicity and, if so, the functional consequences. By decreasing the amount of time required for clinical work, teaching, administration and other departmental duties, this K05 award will enable the applicant to optimize research productivity, continue training junior faculty and fellows in his laboratory, and participate in national and international forums intended to educate the public regarding the neurotoxic potential of substituted amphetamines.