Neuromolecular Drivers of Impulsivity in Addictive Disorders

成瘾性疾病冲动的神经分子驱动因素

基本信息

批准号：
8443304
负责人：
Noelle C Anastasio
金额：
$ 14.28万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443304
关键词：
Abbreviations Abstinence Acute Addictive Behavior Address Agonist Animal Model Attention Deficit Disorder Attenuated Autistic Disorder Behavior Behavior Control Behavioral Binge eating disorder Biological Assay Biology Brain Cell Line Chronic Cocaine Cocaine Abuse Cocaine Dependence Cognitive Complex Cues Cycloserine Data Decision Making Development Development Plans Dimensions Disease Doctor of Philosophy Drug Addiction Drug abuse Drug usage Equilibrium Event Exhibits Faculty Future Gene Silencing Gene Transfer Genetic Techniques Glutamates Goals Health Human Immunohistochemistry Impaired cognition Impulsive Behavior Impulsivity In Vitro Institution Laboratories Link MAPK3 gene Maintenance Medial Mediating Membrane Mentors Molecular Molecular Genetics N-Methyl-D-Aspartate Receptors Nature Neurobiology Neurons Neurosciences Obesity Output Pharmaceutical Preparations Pharmacology Phase Phenotype Phosphorylation Play Positioning Attribute Prefrontal Cortex Prevention Prevention strategy Process Psychopharmacology Rattus Reaction Time Receptor Mediated Signal Transduction Recovery Regulation Relapse Relative (related person)Request for Proposals Research Role Running Self Administration Serotonin Serotonin Receptor 5-HT2C Signal Transduction Staging Students Surface Synapses System Techniques Testing Training Viral Withdrawal addiction career career development cue reactivity design drug seeking behavior in vitro Assay innovation neurochemistry neurotransmission novel prevent programs protein crosslink protein expression public health relevance receptor receptor expression receptor function receptor-mediated signaling skills trait translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本提案要求支持一项全面的培训计划，该计划将使 Noelle C. Anastasio 博士能够拓宽、增强和完善富有成效的独立研究生涯所需的技术技能。我的长期职业目标是在研究密集型学术机构获得终身教职，并建立一个以最终科学目标为重点的研究计划，以了解冲动特征的精神药理学，以推进成瘾的预防和治疗。药物滥用的各个方面，包括吸毒的开始、从随意吸毒到强迫性吸毒的转变、寻求药物行为的维持以及恢复寻求药物的倾向，都与高度的内在冲动相关。中皮质边缘回路内的血清素 (5-HT)2C 受体 (5-HT2CR) 功能失调与成瘾周期的这些阶段以及冲动表型的表现有关。有证据表明，通过同源 5-HT2C 受体 (5-HT2CR) 进行的血清素 (5-HT) 神经传递和通过离子型谷氨酸 N-甲基-D-天冬氨酸受体 (NMDAR) 进行的谷氨酸神经传递在认知和/或冲动和成瘾行为的行为维度，特别是在 mPFC 中，这是决策和目标导向行为不可或缺的区域。因此，mPFC 中 5-HT 和谷氨酸系统之间的相互作用可能会导致可卡因成瘾中出现的认知障碍。我将在 K99 指导阶段（第 1-2 年；目标 1-2）接受来自合作导师团队的多方面培训，其中包括分析受体的分子技术（例如蛋白质交联、细胞系创建、生物响应测定）培训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、颅内微量输注、病毒介导的基因转移）。我还将接受职业发展、资助、实验室工作人员和学生管理以及对运营独立实验室至关重要的财务和规划职责方面的指导。在 R00 独立阶段（第 3-5 年；目标 3-4）提出的研究计划以该培训为基础，更具体地关注 mPFC NMDAR 和 5-HT2CR:NMDAR 异聚复合物作为功能变阻器的神经生物学。固有冲动和可卡因相关复发事件的表达。核心假设是，5-HT2CR 和 NMDAR 功能的平衡驱动 mPFC 输出，而这种平衡的丧失会导致固有的冲动，导致容易发生成瘾性疾病和相关的复发事件。我们将检验这一假设，并揭示导致固有冲动以及与可卡因相关复发事件（例如提示反应性）相关的可卡因诱发冲动的神经分子驱动因素。为了解决这一假设，制定了四个具体目标：目标 1) 确定 mPFC 5-HT2CR 在固有冲动中的作用；目标 2) 确定 mPFC 5-HT2CR 在总冲动/提示反应性中的作用；目标 3) 阐明 mPFC NMDAR 在固有冲动性和总冲动性/提示反应性中的作用；目标 4) 探索 5-HT2CR: NMDAR 复合物的体外和离体生物学。我们将确定神经元 5-HT2CR 和 NMDAR 系统控制冲动，并且重新平衡这些系统可能最终支持以冲动为特征的疾病的行为恢复。总之，这些创新的转化研究将首次系统地探索 5-HT2CR 和 NMDAR 介导的功能在成瘾相关表型中的贡献和相互作用，最终允许设计有针对性的药物治疗方法，以促进戒瘾并防止成瘾性疾病复发。