Neuropharmacology of Abused Stimulants in Nonhuman Primates

描述(由申请者提供)：申请书中描述的职业发展和指导计划将允许申请者继续发展和扩展他的研究生涯，进入新的研究领域，以补充现有的专业领域。具体地说，我将有机会在MRI I功能连接和血管病理学方面获得新的技能和专业知识。我将与Mark Goodman博士合作，为PET开发新的生物标记物，以扩大神经药理靶点，使其超越单胺转运体。我还将在耶克斯野战站启动自我管理和PET神经成像研究，以便通过与马克·威尔逊博士的合作，专注于与行为相关的社会行为和药物使用模式。我计划在五年的支持期内投入75%的努力，以继续推进我在药物滥用研究方面的事业，并加强我作为导师的角色。一旦所有研究方案标准化，大约50%的工作将投入到实验的进行中。拟议的非人类灵长类动物前瞻性研究将记录在使用可卡因期间发生的相关神经化学和功能变化，并应用这些知识来评估消退疗法与药物干预相结合在恢复大脑功能和防止作为药物复发动物模型方面的有效性。这些数据将为未来药物开发的药理靶点提供洞察力，从而加速发现有效的治疗方法。相关研究将提供有关5-羟色胺在调节多巴胺能功能中的基本作用的信息，因为它与可卡因的神经药理学有关。这些在非人类灵长类动物中的翻译研究将确定5-羟色胺系统调节与滥用相关的行为和神经化学效应的有效性。总的来说，行为药理学、体内神经化学和功能神经成像的结合将加强我们对可卡因在非人类灵长类动物中自我给药和恢复的神经生物学机制的理解。另有25%的努力将致力于指导新的独立调查人员。我计划担任两名初级教员的主要导师，并为另外两名教员担任讲师或助理教授的次要导师。通过指导具有广泛专业知识领域的年轻科学家，我将扩大应用于药物成瘾研究的技术和一般方法的广度。剩下的25%没有得到高级科学家研究和导师奖的支持，将致力于大学的行政责任，与该奖项的目标一致的其他与研究有关的工作，包括监督研究生和博士后研究员，以及教育活动。高级科学家研究和导师奖提供的长期承诺和支持将使这些综合技术得以应用于新的研究应用，并为对药物成瘾感兴趣的新的独立调查人员提供有效的指导。 与公共卫生的相关性：本提案的目标是确定治疗兴奋剂滥用和依赖的潜在治疗目标。这些对非人类灵长类动物的翻译研究将确定5-羟色胺系统调节可卡因行为和神经化学效应的有效性，并记录在药物依赖和成瘾发展过程中发生的神经化学、大脑代谢和功能活动的相关变化。此外，将做出重大努力，指导专注于毒瘾研究的新的独立调查人员。

DESCRIPTION (provided by applicant): The career development and mentorship plan described in this application will allow the applicant to continue the development and expansion of his research career into new areas of investigation that complement current areas of expertise. Specifically, I will have the opportunity to acquire new skills and expertise with MRI i functional connectivity and vascular pathology. I will collaborate with Dr. Mark Goodman on the development of novel biomarkers for PET in order to expand neuropharmacological targets beyond monoamine transporters. I also will initiate self-administration and PET neuroimaging studies at the Yerkes Field Station in order to focus on ethologically-relevant models of social behavior and drug use through collaboration with Dr. Mark Wilson. I plan to commit 75% effort during the five-year period of support in order to continue to advance my career in substance abuse research and enhance my role as a mentor. Approximately 50% effort will be devoted to the conduct of experiments once all research protocols are standardized. The proposed prospective studies in nonhuman primates will document the relevant neurochemical and functional changes that occur during cocaine use and apply this knowledge to evaluate the effectiveness of extinction therapy augmented with pharmacological intervention in normalizing brain function and preventing reinstatement as an animal model of drug relapse. These data will provide insights on pharmacological targets for future medications development, thus accelerating the discovery of effective treatments. Related studies will provide information concerning the basic role of serotonin in the regulation of dopaminergic function as it relates to the neuropharmacology of cocaine. These translational studies in nonhuman primates will determine the effectiveness of the serotonin system to modulate the abuse-related behavioral and neurochemical effects cocaine. Collectively, the integration of behavioral pharmacology, in vivo neurochemistry and functional neuroimaging will enhance our understanding of the neurobiological mechanisms involved in cocaine self- administration and reinstatement in nonhuman primates. Another 25% effort will be committed to mentoring of new, independent investigators. I plan to serve as the primary mentor of two junior faculty and as a secondary mentor for two additional faculty at the rank of Instructor or Assistant Professor. Through mentoring young scientists with broad areas of expertise, I will expand the breadth of techniques and general approaches applied to drug addiction research. The remaining 25% effort not supported by the Senior Scientist Research and Mentorship Award will be committed to University administrative responsibilities, other research-related pursuits consistent with the objectives of the award, including oversight of graduate students and postdoctoral fellows, and educational activities. The long-term commitment and support provided by a Senior Scientist Research and Mentorship Award will allow the implementation of these integrated techniques to novel research applications, and provide effective mentorship for new, independent investigators with an interest in drug addiction. PUBLIC HEALTH RELEVANCE: The objective of the present proposal is to identify potential therapeutic targets for the treatment of stimulant abuse and dependence. These translational studies in nonhuman primates will determine the effectiveness of the serotonin system to modulate the behavioral and neurochemical effects cocaine, and document relevant changes in neurochemistry, brain metabolism and functional activity that occur during the progression of drug dependence and addiction. Moreover, significant effort will be committed to the mentorship of new, independent investigators focused on drug addiction research.