CRF and Stress Modulation of Phasic Dopamine Release and Behavior

描述（由申请人提供）：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%的成瘾个体发生复发。复发往往是由于暴露于压力事件而促成的;因此强调了基础科学研究的必要性，以描述压力影响动机行为的神经回路。以前的研究表明，腹侧被盖区（VTA）的多巴胺细胞很好地介导了压力和动机之间的相互作用，但到目前为止，这还没有得到直接的测试。因此，K99/R 00“独立之路奖”提案中研究计划的主要目标是评估与压力相关的肽、厌恶性线索和压力刺激如何直接影响阶段性多巴胺释放，这是与促进动机行为直接相关的多巴胺释放模式。为了实现这一目标，将利用快速扫描循环伏安法结合大脑区域特定的药理学操作来监测执行评估动机的操作性任务的大鼠的阶段性多巴胺释放。在该奖项的指导阶段，候选人将研究如何压力释放的神经肽促肾上腺皮质激素释放因子（CRF）在腹侧被盖区的行为，以影响动机行为和阶段性多巴胺释放在脑桥核奖励相关的刺激自然（目标1）和药物（目标2a）。由于药物暴露会诱导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，因此候选人接下来将评估先前的药物摄入如何影响CRF对天然药物激发行为的影响（目标2b）。在此基础上，压力相关的神经肽如何影响阶段性多巴胺释放和行为，在奖励的独立阶段，随后的实验将直接研究压力（可逃避的和不可避免的）和压力相关的线索如何影响行为和丘脑核中的阶段性多巴胺释放（目标3a）。新出现的证据表明，前额叶皮层和杏仁核中的儿茶酚胺（多巴胺和去甲肾上腺素）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区域中的阶段性儿茶酚胺释放如何受到压力和压力相关线索的影响（目标3b）。 从拟议的工作的结果将不仅是非常重要的成瘾研究，通过产生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，但也将奠定基础，为未来的实验。该项目设计的研究是候选人以前（CRF调节多巴胺神经元放电率的细胞水平分析）和当前工作（检查动机行为期间的阶段性儿茶酚胺释放）的逻辑延伸和协同融合。候选人将在其导师Paul菲利普斯博士的指导下熟练进行药物自我给药研究，并与Jeansok Kim博士协商将通过在压力操作期间纳入伏安法记录来增加候选人的实验曲目。拟议的职业发展计划旨在为候选人提供实现其长期目标的最佳机会，即成为一名独立的终身制研究员，进行神经科学研究，重点是检查行为过程中儿茶酚胺的作用。具体来说，候选人将通过执行拟议的研究，参加华盛顿大学的各种科学研讨会，在科学会议上发表演讲，为研究生级别的课程做关于药物滥用和成瘾的讲座，并参加课程以提高他的科学智力，从而努力实现这一长期目标。候选人将获得职业发展建议，并将在每月与他的主要导师菲利普斯博士和共同导师查尔斯·查夫金博士的联席会议上评估他的进展。菲利普斯博士率先使用长期植入的电极进行伏安法记录，这些电极可以存活数月，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研究中心的氛围有利于培养年轻科学家，最近K99/R 00的获奖者已经过渡到独立的科学事业就是证明。

DESCRIPTION (provided by applicant): 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 proficient 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 repertoire 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 environment 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.