Dorsal striatal mu opioid receptor function and alcohol use

背侧纹状体 mu 阿片受体功能和饮酒

• 批准号: 9260741
• 负责人: Brady Atwood
• 金额: $ 22.2万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260741
• 关键词: Ablation; Address; Affect; Agonist; Air; Alcohol abuse; Alcohol consumption; Alcohols; Alleles; Animal Behavior; Award; Basal Ganglia; Behavior; Brain; Brain region; Cannabinoids; Chronic; Clinical Research; Collaborations; Communication; Communities; Consummatory Behavior; Corpus striatum structure; Coupling; Darkness; Data; Dopamine; Dorsal; Drug usage; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Environment; Equipment and Supplies; Ethanol; Excitatory Synapse; Failure; Future; G-substrate; GTP-Binding Proteins; Genetic; Goals; Impairment; Individual; Infusion procedures; Interneurons; Laboratory Research; Learning; Location; Long-Term Depression; Mediating; Mentors; Mentorship; Mus; Naltrexone; Narcotic Antagonists; National Institute on Alcohol Abuse and Alcoholism; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Opioid; Opioid Receptor; Periodicity; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phase Transition; Play; Postdoctoral Fellow; Process; Protocols documentation; Receptor Activation; Receptor Gene; Receptor Inhibition; Receptor Signaling; Regulation; Research; Research Assistant; Research Technics; Role; Scanning; Science; Scientist; Sensory; Shapes; Signal Transduction; Slice; Specificity; Structure; Synapses; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Time; Training; Transgenic Mice; Translating; Variant; Viral Vector; Work; addiction; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol research; alcohol use disorder; biological research; brain tissue; cell type; cholinergic; design; drinking; drinking behavior; drug of abuse; endogenous opioids; experience; experimental study; graduate student; in vivo; interest; member; mu opioid receptors; neuroadaptation; novel; optogenetics; prevent; public health relevance; receptor; receptor expression; receptor function; recombinase; skills; undergraduate research; vapor

DESCRIPTION (provided by applicant): Dorsal striatal mu opioid receptor function and alcohol use Project Summary: The proposal presented here seeks to better understand the role of mu opioid receptors (MORs) in the dorsal striatum in the transition from alcohol use to abuse. One brain region where MORs may play a significant role is the dorsal striatum, which is a critical structure in the transition from goal-directed to habitual drug use, including alcohol use One of the few effective pharmacological treatments for alcohol use disorders is an opioid receptor antagonist. Additionally, transgenic mice that lack MOR appear to find alcohol aversive. On the other hand, long-term consumption of alcohol may alter the levels and functional coupling of MORs in the dorsal striatum. My preliminary data reveal that long-term alcohol exposure disrupts normal MOR- dependent long-term synaptic plasticity in the dorsal striatum. Thus, there appears to be an interaction between alcohol consumption and the function of MOR in this brain region, which may underlie the transition from drug use to addiction. I hypothesize here that ethanol exposure alters MOR-mediated plasticity at specific striatal synapses and that manipulating MOR function at these same synapses will alter ethanol consummatory behaviors. To test these hypotheses, I propose the following three specific aims. 1. In Specific Aim 1, I wil determine whether alcohol-mediated disruption of dorsal striatal MOR-dependent long-term plasticity of striatal inputs is global or synapse-specific. I will use optogenetics and pharmacology to specifically probe distinct striatal inputs and determine which are MOR-sensitive and whether chronic alcohol disrupts this plasticity. This will provide clues as to what types of input (executive, associative, sensory, etc.) to the dorsal striatum are altered by alcohol use, and provide new hypotheses regarding MOR-regulated effects of alcohol on behavior. 2. In Specific Aim 2, I will identify the effects of alcohol on MOR-mediated regulation of dopaminergic signaling. It is not known how MOR regulates dorsal striatal dopamine release as well as whether this regulation is altered by alcohol exposure. Furthermore, dopaminergic neuroadaptations in the dorsal striatum to prolonged alcohol exposure may result from a disruption of normal, MOR-dependent processes. MORs found on dorsal striatal cholinergic interneurons are in a prime location to modulate dopamine release. Therefore, in this aim I specifically address the hypotheses that MORs on cholinergic interneurons are the critical component of the effects of MOR on dopamine release and that ethanol disrupts this normal MOR-regulated dopamine release. 3. In my final aim, I will pharmacologically and genetically manipulate dorsal striatal MOR function and observe the effects these alterations have on alcohol consumption. I will test the hypothesis that dorsal striatal activation of MOR results in increased alcohol consumption, and conversely that MOR inhibition will reduce ethanol consumption. Additionally, I will use transgenic mice to ablate MOR expression from specific neuron types and observe whether these genetically modified mice still consume alcohol. These experiments will reveal whether MORs in the dorsal striatum, and more specifically in distinct cell types, control alcohol consummatory behavior. Throughout my time as an undergraduate research assistant, graduate student, and postdoctoral fellow, I have had an intense interest in how drugs of abuse change synapses in the brain. I have had the privilege of working with great scientists such as Drs. Ken Mackie and David Lovinger, among others, who have taught me invaluable skills of not just research techniques, but engaging in hypothesis-driven science. These mentors have taught me to ask many questions, design careful and focused experiments, and critically interpret data. In addition, they have provided me with many opportunities to direct the course of the work I performed, allowing me to fail at times and learn from those failures. I am a better scientist because of the mentorship of these individuals and my many other colleagues. During the mentored phase of this award, I will have the support of the Division of Intramural Clinical and Biological Research and will be under the mentorship of Dr. Lovinger. I have a number of highly qualified colleagues that are readily available to teach me the new techniques necessary to accomplish the work presented here. As a result of the mentored phase of this project, I will learn and become proficient in new skills such as fast-scan cyclic voltammetry, ethanol administration paradigms, and infusion of drugs into brain tissue. I will also develop skills that I have limited training in, such as stereotaxic surgeries and optogenetic protocols. In addition, at NIAAA I have access to high quality research equipment and supplies that will allow me to achieve the work that will be performed during the mentored phase. Throughout the mentored and transition phases, I will gain additional mentoring experience and skills that will enable me to independently oversee my own research laboratory in the future. Furthermore, I am in close association with many experts in the field of alcohol research from whom I can learn much and become a fully integrated member of this research community. I am confident that with Dr. Lovinger's principal mentorship, the additional mentorship of a committee of select colleagues, and the institutional environment at NIAAA, I will be able to achieve my goals of becoming a fully independent neuroscientist.

描述(申请人提供)：背侧纹状体u阿片受体功能和酒精使用项目摘要：这里提出的建议旨在更好地了解背侧纹状体u阿片受体(MORS)在从酒精使用到滥用的转变过程中的作用。MORS可能发挥重要作用的一个大脑区域是背侧纹状体，它是从目标导向向习惯性药物使用(包括酒精使用)过渡的关键结构。阿片受体拮抗剂是治疗酒精使用障碍的为数不多的有效药物之一。此外，缺乏吗啡的转基因小鼠似乎不喜欢酒精。另一方面，长期饮酒可能会改变背侧纹状体MORS的水平和功能偶联。我的初步数据显示，长期酒精暴露扰乱了背侧纹状体正常的依赖吗啡的长期突触可塑性。因此，酒精消费和大脑这一区域的MOR功能之间似乎存在相互作用，这可能是从吸毒到成瘾转变的基础。我在这里假设，酒精暴露改变了特定纹状体突触上MOR介导的可塑性，并且操纵这些相同突触上的MOR功能将改变乙醇的消耗行为。为了检验这些假设，我提出了以下三个具体目标。1.在具体目标1中，我将确定酒精对纹状体背侧吗啡依赖的长期可塑性的破坏是全局性的还是突触专一性的。我将使用光遗传学和药理学来专门探索不同的纹状体输入，并确定哪些是更敏感的，以及长期酒精是否会破坏这种可塑性。这将提供关于什么的线索 输入类型(执行型、关联型、感觉型等)对背侧纹状体的影响因酒精使用而改变，并为酒精对行为的更多调节效应提供了新的假设。2.在具体目标2中，我将确定酒精对吗啡介导的多巴胺能信号调节的影响。目前尚不清楚MOR如何调节背侧纹状体多巴胺的释放，以及这一调节是否会因酒精暴露而改变。此外，背侧纹状体对长期酒精暴露的多巴胺能神经适应可能是由于正常的、吗啡依赖的过程被破坏所致。在背侧纹状体胆碱能中间神经元上发现的MORS是调节多巴胺释放的最佳位置。因此，在这个目的中，我特别提出的假设是，胆碱能中间神经元上的MORS是MOR影响多巴胺释放的关键成分，而乙醇破坏了这种正常的MOR调节的多巴胺释放。3.在我的最终目标中，我将从药物和遗传方面操纵背侧纹状体的MOR功能，并观察这些变化对饮酒的影响。我将验证这样一种假设，即激活背侧纹状体MOR会导致酒精消耗量增加，反过来，抑制MOR会减少酒精消耗量。此外，我将使用转基因小鼠来消除特定神经元类型的MOR表达，并观察这些转基因小鼠是否仍然饮酒。这些实验将揭示背侧纹状体中的MORS，更具体地说，在不同类型的细胞中，是否控制酒精消耗行为。在我担任本科生研究助理、研究生和博士后研究员的整个时间里，我对滥用药物如何改变大脑中的突触有着浓厚的兴趣。我有幸与Ken Mackie博士和David Lovinger博士等伟大的科学家一起工作，他们教会了我宝贵的技能，不仅是研究技术，还包括假说驱动的科学。这些导师教会了我提出许多问题，设计仔细而有重点的实验，以及批判性地解读数据。此外，它们为我提供了许多机会来指导我所做工作的进程，使我能够时不时地失败，并从失败中吸取教训。由于这些人和我的许多其他同事的指导，我成为了一名更好的科学家。在这个奖项的指导阶段，我将得到校内临床和生物研究部的支持，并将在洛文格博士的指导下。我有一些非常合格的同事，他们随时可以教我完成这里介绍的工作所需的新技术。作为这个项目的指导阶段的结果，我将学习并精通新的技能，如快速扫描循环伏安法、乙醇给药范例和向脑组织中注入药物。我还将发展我只接受过有限培训的技能，如立体定向手术和光遗传方案。此外，在NIAAA，我可以获得高质量的研究设备和用品，这将使我能够完成将在指导阶段完成的工作。在指导和过渡阶段，我将获得更多的指导经验和技能，使我能够在未来独立监督我自己的研究实验室。此外，我与酒精研究领域的许多专家保持着密切的联系，我可以从他们那里学到很多东西，并成为这个研究社区的完全融入的一员。我相信，有了洛文格博士的主要指导、一个精选同事委员会的额外指导以及NIAAA的机构环境，我将能够实现我成为一名完全独立的神经科学家的目标。