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

基本信息

批准号：
8508006
负责人：
Matthew J. Wanat
金额：
$ 10.81万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2013-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508006
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 Environment Event 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 public health relevance reinforcer research study response symposium transmission process

项目摘要

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.

描述（由申请人提供）：与治疗药物成瘾有关的更艰巨的问题之一是复发的发生率很高，据报道，这在多达90％的上瘾者中发生。暴露于压力事件的情况通常会引起复发。因此，强调了基础科学研究的需求，以表征压力影响动机行为的神经回路。先前的研究表明，腹侧对盖区域（VTA）的多巴胺细胞位置很好地介导了压力和动机之间的相互作用，但至今尚未直接测试。因此，在此K99/R00“独立途径奖励”提案中，研究计划的主要目标是评估与压力相关的肽，厌恶提示和压力刺激如何直接影响变质多巴胺的释放，这是多巴胺释放的模式与促进动机行为有关。为了解决这一目标，将利用快速扫描的循环伏安法监测阶段性多巴胺释放，并结合大脑区域的特定药理操作，在执行可评估动机的操作任务的大鼠中。在奖励的指导阶段，候选人将研究与压力释放的神经肽皮质激素释放因子（CRF）如何作用于VTA，以影响动机的行为和振容核中的运动性多巴胺的释放，以奖励与自然相关的刺激（目标） 1）和药物（AIM 2A）增强剂。由于药物暴露会引起多巴胺系统中的突触变化，包括CRF与多巴胺神经元的相互作用，因此候选人接下来将评估先前的药物摄入如何影响CRF对天然增强剂的动机行为的影响（AIM 2B）。凭借与压力相关的神经肽如何影响阶段多巴胺释放和行为的基础，随后在奖励的独立阶段进行了随后的实验，将直接研究压力（可逃避和不可避免的可逃避和不可避免）和应力相关线索如何影响行为和核中核中释放的压力，伏anc（AIM 3A）。新兴的证据表明，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）释放也与介导对压力的反应有关，因此候选者还将如何解决这些大脑中的质量儿茶酚胺在这些大脑区域的释放如何受到压力和压力相关的提示的影响。（AIM 3B）。提议的工作的发现不仅将对成瘾研究非常重要，这是通过对压力，动机和阶段性儿茶酚胺释放之间相互作用的有价值的发现，而且还将为将来的实验奠定基础。该项目中设计的研究是对候选人先前的（CRF调节多巴胺神经元发射率的细胞水平分析）的逻辑扩展和协同合并，并进行了当前的工作（检查动机行为期间的相位catecholamine释放）。在他的导师保罗·菲利普斯（Paul Phillips）的建议下，候选人将熟练地熟练地进行药物自我管理研究，并通过在压力操纵期间合并伏安玛特（Jeansok Kim）的咨询，以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最佳机会，以实现他成为独立的终身训练研究员进行神经科学研究的长期目标，该研究人员致力于研究儿茶酚胺在行为中的作用。具体而言，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，在科学会议上介绍，为研究生级别的有关药物滥用和成瘾的研究生课程提供讲座，并上课以增强课程来提高候选人的长期目标。他的科学智力。候选人将获得职业发展咨询服务，并将在他与他的主要导师菲利普斯博士兼同事查尔斯·查文金（Charles Chavkin）的每月联合会议上进行评估。 Phillips博士使用慢性植入的电极开创了伏安法记录，这些电极持续了几个月，因此为执行这些实验提供了一个很好的环境。此外，华盛顿大学和通过药物成瘾研究中心的气氛有利于发展年轻科学家，这是由K99/R00的最新获奖者证明，他们已过渡到独立的科学职业。