Studies of Substituted Amphetamine Neurotoxicity

替代安非他明神经毒性的研究

• 批准号: 6880559
• 负责人: GEORGE A RICAURTE
• 金额: $ 12.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880559
• 关键词: 3,4 methylenedioxymethamphetamine; Primates; Rodentias; amphetamines; dopamine; drug abuse; human subject; methamphetamine; neuropharmacology; neurotoxicology; neurotoxins; positron emission tomography; serotonin; tissue /cell culture

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.

描述（由申请人提供）： 这项修订后的高级科学家奖（K05）的申请被提交，以使申请人能够在接下来的五年内继续从事滥用药物滥用研究。申请人实验室的研究集中于取代的苯丙胺衍生物（MDMA，甲基苯丙胺）及其在动物以及可能的人类中有选择性损害脑血清素和/或多巴胺神经元的倾向。这项研究的长期目标是更好地定义人类替代苯丙胺暴露的风险和后果，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，无论是在健康和疾病中。此外，这项研究旨在确定取代的苯丙胺损害脑氨基神经元的机制，因为这些信息可能会深入了解人类神经退行性疾病中神经元丧失的过程。 多种方法用于实现这些目标。在孤立的系统（基因微阵列，突触体和培养细胞）和完整动物（啮齿动物）中进行的研究探索了替代的苯丙胺神经毒性的机制，确定了对神经毒性表达的关键分子要求，并表征了短期和长期反应的角质蛋白和多巴胺神经蛋白神经蛋白神经蛋白的反应。非人类灵长类动物的研究试图更准确地衡量替代苯丙胺对人类构成的风险，并开发和验证方法来检测人类替代的苯丙胺神经毒性的后果。人类的研究（包括分子PET成像，药理挑战，神经精神病学评估，认知测试和多性学评估评估）旨在确定使用替代苯丙胺的人是否发展出神经毒性，如果是这样，则功能后果是否会产生功能后果。 通过减少临床工作，教学，行政和其他部门职责所需的时间，该K05奖将使申请人能够优化研究生产力，继续在其实验室中培训初级教师和研究员，并参加国家和国际论坛，并参与旨在对公众进行有关替代的固定胺神经毒性潜力的教育。