Neuromolecular Drivers of Impulsivity in Addictive Disorders

项目总结/摘要 这项建议要求支持一项全面的培训计划，使Noelle C. Anastasio博士， 扩大，增强和完善技术技能，这是必要的生产性独立研究 事业我的长期职业目标是在一所研究密集型的大学获得一个终身教职。 机构和建立一个研究计划，重点是最终的科学目标，以了解 精神药理学的冲动特质，以促进预防和治疗成瘾。各个方面 药物滥用的影响，包括开始吸毒、从随意吸毒到强迫吸毒的转变、 寻求毒品行为的维持以及恢复寻求毒品的倾向与高 内在冲动的程度5-羟色胺（5-HT）2C受体（5-HT 2CR）功能失调 中皮质边缘回路与成瘾周期的这些阶段有关， 冲动型的表现。有证据表明，血清素（5-HT）神经传递 通过其同源5-HT 2C受体（5-HT 2CR）和谷氨酸神经传递，通过离子型 谷氨酸N-甲基-D-天冬氨酸受体（NMDAR）在认知和/或行为中起关键作用 冲动和成瘾行为的维度，特别是在mPFC中，这是决策不可或缺的区域 和目标导向的行为因此，mPFC中5-HT和谷氨酸系统之间的相互作用可能 导致了可卡因成瘾的认知障碍我将在这期间接受多方面的培训。 K99辅导阶段（1-2年级;目标1-2），由一组合作导师提供，包括以下方面的培训 分子技术（例如，蛋白质交联、细胞系的产生、生物响应测定）来分析 受体亚细胞定位和信号转导调节，以及复杂的行为 神经科学/药理学/分子遗传学技术（例如，免疫组织化学，颅内 微输注、病毒介导的基因转移）。我还将接受职业发展方面的指导， 实验室工作人员和学生管理以及财务和规划职责， 拥有独立的实验室。R 00独立阶段提出的研究计划 （3-5年;目标3-4）在此培训的基础上，更具体地关注mPFC的神经生物学 NMDAR和5-HT 2CR：NMDAR异聚体复合物作为功能性变阻器在表达固有的 冲动和可卡因相关复发事件。中心假设是5-HT 2CR和 NMDAR功能驱动mPFC输出，失去这种平衡会导致固有的冲动， 导致易患成瘾性疾病和相关的复发事件。我们将测试 这一假设，并揭示了神经分子驱动器负责固有的冲动，以及可卡因- 与可卡因相关的复发事件相关的诱发冲动（例如，线索反应性）。为了解决这个 假设，四个具体的目标已经制定：目标1）建立的作用mPFC 5-HT 2CR在固有的 冲动性;目的2）确定mPFC 5-HT 2CR在聚集冲动性/线索反应性中的作用;目的3）阐明 mPFC NMDAR在固有冲动性和聚集冲动性/线索反应性中的作用;目的4）探索 5-HT 2CR：NMDAR复合物的体外和离体生物学。我们将确定神经元5-HT 2CR和 NMDAR系统控制冲动，重新平衡这些系统可能最终支持行为 以冲动为特征的疾病的恢复。总之，这些创新的翻译研究将是第一个 系统探讨5-HT 2CR和NMDAR介导的功能在成瘾中的作用和相互作用， 相关表型，最终允许设计靶向药物治疗，以促进 戒断和防止成瘾性疾病复发。

PROJECT SUMMARY/ABSTRACT This proposal requests support for a comprehensive training plan that will enable Noelle C. Anastasio, Ph.D., to broaden, enhance, and refine technical skills that are necessary for a productive independent research career. My long-term career goal is to obtain a tenure-track faculty position at a research-intensive academic institution and build a research program focused upon the ultimate scientific goal to understand the psychopharmacology of the impulsivity trait to advance prevention and treatment of addiction. Various aspects of drug abuse, including the initiation of drug-taking, the transition from casual to compulsive drug use, the maintenance of drug-seeking behaviors as well as the penchant to reinstate drug-seeking correlate with high levels of inherent impulsivity. Dysregulation in serotonin (5-HT) 2C receptor (5-HT2CR) function within the mesocorticolimbic circuit has been implicated in these stages of the addiction cycle as well as the manifestation of the impulsive phenotype. There is evidence that both serotonin (5-HT) neurotransmission through its cognate 5-HT2C receptor (5-HT2CR) and glutamate neurotransmission through the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) play key roles in the cognitive and/or behavioral dimensions of impulsivity and addictive behaviors, especially in the mPFC, a region integral to decision-making and goal-directed behavior. Thus, the interaction between 5-HT and glutamate systems in the mPFC may contribute to the cognitive impairments seen in cocaine addiction. I will receive multifaceted training during the K99 mentored phase (Years 1-2; Aims 1-2) from a team of collaborating mentors that includes training in molecular techniques (e.g., protein crosslinking, creation of cell lines, bioresponsive assays) to analyze receptor subcellular localization and signal transduction regulation, as well as sophisticated behavioral neuroscience/pharmacology/molecular genetics techniques (e.g., immunohistochemistry, intracranial microinfusion, viral-mediated gene transfer). I will also receive mentoring in career development, grantsmanship, laboratory staff and student management and fiscal and planning responsibilities critical to running an independent laboratory. The research plan that is proposed during the R00 independent phase (Years 3-5; Aims 3-4) builds on this training to focus more specifically on the neurobiology of the mPFC NMDAR and the 5-HT2CR:NMDAR heteromeric complex as functional rheostats in expression of inherent impulsivity and cocaine-associated relapse events. The central hypothesis is that a balance of 5-HT2CR and NMDAR function drives mPFC output and that the loss of this balance contributes to inherent impulsivity, leading to vulnerability for the development of addictive disorders and associated relapse events. We will test this hypothesis and uncover neuromolecular drivers responsible for inherent impulsivity as well as the cocaine- evoked impulsivity in relation to cocaine-associated relapse events (e.g., cue reactivity). To address this hypothesis, four specific aims have been formulated: Aim 1) establish the role for mPFC 5-HT2CR in inherent impulsivity; Aim 2) establish the role for mPFC 5-HT2CR in aggregate impulsivity/cue reactivity; Aim 3) elucidate the role for mPFC NMDAR in inherent impulsivity and aggregate impulsivity/cue reactivity; Aim 4) explore the biology of the 5-HT2CR:NMDAR complex in vitro and ex vivo. We will determine that neuronal 5-HT2CR and NMDAR systems govern impulsivity and that rebalancing these systems may ultimately support behavioral recovery in disorders marked by impulsivity. Together, these innovative translational studies will be the first to systemically explore the contribution and interaction of 5-HT2CR- and NMDAR-mediated function in addiction- relevant phenotypes, ultimately allowing for the design of targeted pharmacotherapeutics to promote abstinence and prevent relapse in addictive disorders.