Neuromolecular Drivers of Impulsivity in Addictive Disorders

成瘾性疾病冲动的神经分子驱动因素

• 批准号: 8601060
• 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
• 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/8601060
• 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

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)：本提案请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、增强和完善为富有成效的独立研究生涯所必需的技术技能。我的长期职业目标是在一家研究密集型学术机构获得终身教职，并建立一个专注于终极科学目标的研究项目，以了解冲动特质的精神药理学，以促进成瘾的预防和治疗。药物滥用的各个方面，包括开始吸毒、从随意吸毒过渡到强迫吸毒、维持吸毒行为以及恢复吸毒的倾向，都与高度的内在冲动有关。5-羟色胺(5-羟色胺)2C受体(5-HT2CR)功能失调在成瘾循环的这些阶段以及冲动性表型的表现中被认为与中皮质边缘回路中的功能失调有关。有证据表明，通过其同源5-HT2C受体(5-HT2CR)的5-羟色胺(5-HT)神经传递和通过离子亲性谷氨酸N-甲基-D-天冬氨酸受体(NMDAR)的谷氨酸神经传递在冲动和成瘾行为的认知和/或行为维度中发挥关键作用，特别是在mPFC，这是决策和目标定向行为不可或缺的区域。因此，mPFC中5-羟色胺和谷氨酸系统之间的相互作用可能有助于可卡因成瘾引起的认知障碍。在K99指导阶段(1-2年；AIMS 1-2)，我将接受一个合作导师团队的多方面培训，其中包括分子技术(例如蛋白质交联、细胞系创建、生物反应分析)以分析受体亚细胞定位和信号转导调节，以及先进的行为神经科学/药理学/分子遗传学技术(例如免疫组织化学、颅内显微输注、病毒介导的基因转移)。我还将接受职业发展、助学金、实验室工作人员和学生管理方面的指导，以及对运营独立实验室至关重要的财务和规划责任。在R00独立阶段(3-5年；AIMS 3-4)提出的研究计划建立在这一培训的基础上，以更具体地关注mPFC NMDAR和5-HT2CR：NMDAR异构体复合体作为表达固有冲动和可卡因相关复发事件的功能调节剂的神经生物学。中心假说是5-HT2CR和NMDAR功能的平衡驱动mPFC的输出，这种平衡的丧失导致固有的冲动，导致容易发生成瘾障碍和相关的复发事件。我们将测试这一假说，并发现神经分子驱动因素负责固有的冲动以及与可卡因相关的复发事件(例如，线索反应性)的可卡因诱发的冲动。为了解决这一假说，已经制定了四个具体目标：目的1)确定mPFC 5-HT2CR在固有冲动性中的作用；目的2)确定mPFC 5-HT2CR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-HT2CR：NMDAR复合体在体外和体外的生物学作用。我们将确定神经元5-HT2CR和NMDAR系统支配冲动，重新平衡这些系统最终可能支持以冲动为标志的障碍的行为恢复。总之，这些创新的翻译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，最终允许设计靶向药物疗法来促进戒断和防止成瘾障碍的复发。