CRF and Stress Modulation of Phasic Dopamine Release and Behavior

项目摘要 与治疗药物成瘾相关的更令人生畏的问题之一是复发的高发生率， 据报道，高达90%的成瘾者会发生这种情况。复发往往是由 暴露于压力事件;因此强调需要基础科学研究来表征神经系统 压力影响动机行为的回路。以前的研究表明，大脑中的多巴胺细胞 腹侧被盖区（VTA）是调解压力和动机之间的相互作用，但 目前尚未直接测试。因此，本K99/R00研究计划的主要目标 “独立之路奖”的建议是评估与压力相关的肽，厌恶的线索， 压力刺激直接影响多巴胺阶段性释放，这是多巴胺直接释放的模式 与促进动机行为有关。为了实现这一目标，快速扫描循环伏安法将是 用于监测阶段性多巴胺释放， 操纵大鼠执行评估动机的操作性任务。在辅导阶段， 获奖，候选人将研究如何压力释放神经肽促肾上腺皮质激素释放因子（CRF） 在腹侧被盖区起作用，影响主动行为和丘脑核中的阶段性多巴胺释放， 奖励相关的刺激，自然（目标1）和药物（目标2a）。因为药物暴露会导致 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， 候选人接下来将评估先前的药物摄入如何影响CRF对自然行为的动机行为的影响。 （目标2b）。有了这个基础，压力相关的神经肽如何影响时相多巴胺 释放和行为，随后的实验在独立阶段的奖励将直接 研究压力（可逃避的和不可避免的）和与压力相关的线索如何影响行为和阶段 多巴胺在丘脑核中的释放（Aim 3a）。新的证据表明， （多巴胺和去甲肾上腺素）的释放在前额皮质和杏仁核也参与介导 对压力的反应，所以候选人也将解决如何阶段性的儿茶酚胺释放在这些大脑 区域受到压力和压力相关线索的影响（目标3b）。 这项工作的发现不仅对成瘾研究具有重要意义， 有价值的发现之间的相互作用的压力，动机，和阶段性的儿茶酚胺释放，但也将 为今后的试验打下基础。本项目设计的研究是一个逻辑延伸， 候选人先前的协同合并（CRF调节多巴胺的细胞水平分析 神经元放电率）和当前的工作（检查激励行为期间的阶段性儿茶酚胺释放）。的 在导师的指导下，候选人将能够熟练地进行药物自我给药研究 博士保罗菲利普斯，并咨询博士Jeansok金将添加到候选人的实验报告， 在应力操作期间并入伏安法记录。拟议的职业发展计划是 旨在为候选人提供实现其长期目标的最佳机会， 独立的终身研究员进行神经科学研究，重点是检查的作用， 行为中的儿茶酚胺具体来说，候选人将通过执行这一长期目标而努力 拟议的研究，参加各种科学研讨会在华盛顿大学，提出在 科学会议，在研究生课程上讲授药物滥用和成瘾问题， 课程，以提高他的科学智力。候选人将获得职业发展建议， 在与他的主要导师菲利普斯博士和共同导师 查尔斯·查夫金菲利普斯博士开创了使用长期植入电极的伏安法记录， 几个月内仍然可以存活，因此提供了一个极好的环境来进行这些实验。 此外，华盛顿大学和药物成瘾中心的气氛 最近K99/R00的获奖者证明，研究有利于培养年轻科学家 他们已经过渡到独立的科学事业。

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.