CRF and Stress Modulation of Phasic Dopamine Release and Behavior

CRF 和阶段性多巴胺释放和行为的压力调节

• 批准号: 8796749
• 负责人: Matthew J. Wanat
• 金额: $ 24.85万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8796749
• 关键词: Address; Affect; Amygdaloid structure; Attenuated; Award; Basic Science; Behavior; Behavioral; Brain region; Catecholamines; Cells; Cocaine; Complex; Consult; Corticotropin-Releasing Hormone; Cues; Data; Development Plans; Dopamine; Dose; Drug Addiction; Drug Exposure; Drug abuse; Experimental Designs; Exposure to; Food; Foundations; Future; Goals; Implanted Electrodes; Incidence; Individual; Infusion procedures; Intake; Joints; Medial; Mediating; Mental disorders; Mentors; Monitor; Motivation; Neural Pathways; Neurons; Neuropeptides; Neurosciences Research; Norepinephrine; Nucleus Accumbens; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; Phase; Physiology; Prefrontal Cortex; Rattus; Recording of previous events; Reinforcement Schedule; Relapse; Reporting; Research; Research Design; Research Personnel; Rewards; Rodent; Rodent Model; Role; Scanning; Scientist; Self Administration; Signal Transduction; Stimulus; Stress; Stressful Event; Synapses; Testing; Training; Universities; Ventral Tegmental Area; Washington; Work; addiction; base; career; career development; design; dopamine system; dopaminergic neuron; experience; in vivo; lectures; meetings; motivated behavior; neural circuit; neuroadaptation; neuromechanism; neurotransmitter release; planetary Atmosphere; reinforcer; research study; response; symposium; transmission process

Project Summary One of the more daunting problems associated with treating drug addiction is the high incidence of relapse, which has been reported to occur in up to 90% of addicted individuals. Relapse is often precipitated by exposure to stressful events; thus highlighting the need for basic science research to characterize the neural circuits by which stress affects motivated behavior. Previous studies suggest that the dopamine cells of the ventral tegmental area (VTA) are well situated to mediate the interaction between stress and motivation, but to date this has not been directly tested. Therefore, the primary goal of the research plan in this K99/R00 'Pathway to Independence Award' proposal is to assess how stress-related peptides, aversive cues, and stressful stimuli directly affect phasic dopamine release, which is the pattern of dopamine release directly associated with promoting motivated behavior. To address this goal, fast-scan cyclic voltammetry will be utilized to monitor phasic dopamine release in combination with brain-region specific pharmacological manipulations in rats performing operant tasks that assess motivation. During the mentored phase of the award, the candidate will examine how the stress-released neuropeptide corticotropin-releasing factor (CRF) acts in the VTA to affect motivated behavior and phasic dopamine release in the nucleus accumbens to reward-related stimuli for natural (Aim 1) and drug (Aim 2a) reinforcers. Because drug exposure induces synaptic changes within the dopamine system, including how CRF interacts with dopamine neurons, the candidate will next assess how prior drug intake influences CRF's effect on motivated behavior for natural reinforcers (Aim 2b). With this foundation of how a stress-related neuropeptide affects phasic dopamine release and behavior, subsequent experiments during the independent phase of the award will directly examine how stress (escapable and inescapable) and stress-associated cues affect behavior and phasic dopamine release in the nucleus accumbens (Aim 3a). Emerging evidence suggests that catecholamine (dopamine and norepinephrine) release in the prefrontal cortex and amygdala are also involved with mediating the response to stress, so the candidate will also address how phasic catecholamine release in these brain regions is affected by stress and stress-associated cues (Aim 3b). The findings from the proposed work will not only be of great importance to addiction research by yielding valuable findings on the interaction between stress, motivation, and phasic catecholamine release, but will also lay a foundation for future experimentation. The research designed in this project is a logical extension and synergistic amalgamation of the candidate's previous (cellular level analysis of CRF modulating dopamine neuron firing rate) and current work (examining phasic catecholamine release during motivated behavior). The candidate will become proficent in performing drug self-administration studies under the advising of his mentor Dr. Paul Phillips, and consulting with Dr. Jeansok Kim will add to the candidate's experimental repitoire by incorporating voltammetry recordings during stress manipulations. The proposed career development plan is designed to afford the candidate the best opportunity of achieving his long-term goal of becoming an independent tenure-track investigator conducting neuroscience research focused on examining the role of catecholamines during behavior. Specifically, the candidate will strive toward this long-term goal by performing the proposed research, attending various scientific seminars at the University of Washington, presenting at scientific conferences, giving lectures to graduate level classes about drug abuse and addiction, and taking classes to enhance his scientific intellect. The candidate will receive career development advising and will be evaluated on his progress in his monthly joint meetings with his primary mentor, Dr. Phillips and co-mentor, Dr. Charles Chavkin. Dr. Phillips pioneered voltammetry recordings using chronically implanted electrodes that remain viable for months, and as such provides an excellent enviroment to perform these experiments. Furthermore, the atmosphere at the University of Washington and through the Center for Drug Addiction Research is conducive for developing young scientists, as evidenced by the recent awardees of the K99/R00 whom have transitioned to independent scientific careers.

项目摘要 与治疗药物成瘾有关的最艰巨的问题之一是复发的发生率很高， 据报道，该成瘾个人中最多发生。复发通常由 暴露于压力事件；因此强调了基础科学研究的需求以表征神经 压力影响动机行为的电路。先前的研究表明， 腹侧对段区域（VTA）的位置良好，可以介导压力与动机之间的相互作用，但要介导 日期尚未直接测试。因此，在此K99/R00中研究计划的主要目标 “独立之途径”提案是评估与压力相关的肽，厌恶提示和 压力性刺激直接影响阶段多巴胺释放，这是多巴胺释放的模式 与促进动机行为有关。为了解决这个目标，快速扫描的循环伏安法将是 用于监测阶段多巴胺释放与大脑区域的药理结合 在执行评估动机的操作任务的大鼠中操纵。在指导的阶段 奖项，候选人将检查压力发行的神经肽皮质激素释放因子（CRF）如何 在VTA中作用，影响动机行为和伏核中的阶段性多巴胺释放到 自然（AIM 1）和药物（AIM 2A）增强剂的奖励相关刺激。因为药物暴露会引起 多巴胺系统内的突触变化，包括CRF如何与多巴胺神经元相互作用， 候选人接下来评估先前的药物摄入如何影响CRF对自然动机行为的影响 增强剂（AIM 2B）。凭借与压力相关的神经肽如何影响阶段多巴胺的基础 释放和行为，奖励独立阶段的随后实验将直接 检查压力（可逃避和不可避免的）和应力相关线索如何影响行为和阶段 在伏隔核中释放多巴胺（AIM 3A）。新兴证据表明儿茶酚胺 （多巴胺和去甲肾上腺素）在前额叶皮层和杏仁核中释放也参与介导 对压力的反应，因此候选人还将解决这些大脑中的阶段儿茶酚胺如何释放 区域受压力和应力相关线索的影响（AIM 3B）。 提议的工作的发现不仅将对成瘾研究非常重要 关于压力，动机和阶段性儿茶酚胺释放之间相互作用的宝贵发现，但也将 为将来的实验奠定基础。该项目设计的研究是逻辑扩展， 候选人先前的协同合并（CRF调节多巴胺的细胞水平分析 神经元的发射率）和当前的工作（在动机行为过程中检查阶段性儿茶酚胺释放）。这 在他的导师的建议下，候选人将熟练地进行药物自我管理研究 保罗·菲利普斯（Paul Phillips）博士，并与Jeansok Kim博士进行咨询，将增加候选人的实验性申请。 在应力操纵过程中结合伏安法记录。拟议的职业发展计划是 旨在为候选人提供实现自己的长期目标的最佳机会 进行神经科学研究的独立终身轨道调查员着重研究 行为过程中的儿茶酚胺。具体而言，候选人将通过执行这一长期目标努力 拟议的研究，参加了华盛顿大学的各种科学研讨会，演讲 科学会议，为研究生级的班级提供有关药物滥用和成瘾的课程，并接受 课堂以增强他的科学智力。候选人将获得职业发展咨询，并将 评估了他在与他的主要导师菲利普斯博士和同事博士的每月联合会议上的进步。 查尔斯·查文金（Charles Chavkin）。菲利普斯博士使用长期植入的电极开创了伏安法记录 保持几个月的活力，因此为执行这些实验提供了出色的环境。 此外，华盛顿大学和吸毒中心的气氛 研究有利于发展年轻科学家，这是K99/R00的最新获奖者所证明的 已经过渡到独立科学职业的人。