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: 9222263
• 负责人: Brady Atwood
• 金额: $ 24.89万
• 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/9222263
• 关键词: Ablation; Address; Affect; Agonist; Air; Alcohol abuse; Alcohol consumption; Alcohols; Alleles; Animal Communication; Award; Basal Ganglia; Behavior; Brain; Brain region; Breeding; Cannabinoids; Cell Nucleus; Chronic; Clinical Research; Collaborations; Communities; Consummatory Behavior; Corpus striatum structure; Coupling; Data; Dopamine; Dorsal; Drug usage; Educational process of instructing; Electrophysiology (science); Environment; Equipment and Supplies; Ethanol; Excitatory Synapse; Failure; Future; GTP-Binding Proteins; Genetic; Goals; Health; 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; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phase Transition; Play; Postdoctoral Fellow; Process; Protocols documentation; Qualifying; 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 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; graduate student; in vivo; interest; member; mu opioid receptors; neuroadaptation; novel; optogenetics; prevent; receptor; receptor expression; receptor function; recombinase; research study; 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（由申请人提供）：背侧纹状体 mu 阿片受体功能和饮酒 项目摘要：此处提出的提案旨在更好地了解背侧纹状体 mu 阿片受体 (MOR) 在从饮酒到滥用的转变中的作用。 MOR 可能发挥重要作用的一个大脑区域是背侧纹状体，它是从目标导向药物使用（包括酒精使用）过渡到习惯性药物使用的关键结构阿片受体是治疗酒精使用障碍的少数有效药物之一对手。此外，缺乏 MOR 的转基因小鼠似乎厌恶酒精。另一方面，长期饮酒可能会改变背侧纹状体中 MOR 的水平和功能耦合。我的初步数据表明，长期接触酒精会破坏背侧纹状体中正常的 MOR 依赖性长期突触可塑性。因此，饮酒与该大脑区域的 MOR 功能之间似乎存在相互作用，这可能是从吸毒到成瘾的转变的基础。我在此假设，乙醇暴露会改变特定纹状体突触处 MOR 介导的可塑性，并且操纵这些相同突触处的 MOR 功能将改变乙醇的完美行为。为了检验这些假设，我提出以下三个具体目标。 1. 在具体目标 1 中，我将确定酒精介导的背侧纹状体 MOR 依赖性纹状体输入长期可塑性破坏是全局性的还是突触特异性的。我将利用光遗传学和药理学来专门探测不同的纹状体输入，并确定哪些输入对 MOR 敏感，以及慢性酒精是否会破坏这种可塑性。这将提供关于什么的线索 背侧纹状体的输入类型（执行、联想、感觉等）会因饮酒而改变，并提供关于酒精对行为的 MOR 调节作用的新假设。 2. 在具体目标 2 中，我将确定酒精对 MOR 介导的多巴胺能信号传导调节的影响。目前尚不清楚 MOR 如何调节背侧纹状体多巴胺的释放，以及这种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 MOR 依赖性过程的破坏造成的。在背侧纹状体胆碱能中间神经元上发现的 MOR 处于调节多巴胺释放的主要位置。因此，在这个目标中，我特别提出了这样的假设：胆碱能中间神经元上的 MOR 是 MOR 对多巴胺释放影响的关键组成部分，并且乙醇会破坏这种正常的 MOR 调节的多巴胺释放。 3. 在我的最终目标中，我将从药理学和基因角度操纵背侧纹状体 MOR 功能，并观察这些改变对饮酒的影响。我将检验以下假设：MOR 的背侧纹状体激活会导致酒精消耗增加，相反，MOR 抑制会减少乙醇消耗。此外，我将使用转基因小鼠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 MOR，特别是不同细胞类型中的 MOR 是否控制酒精的完美行为。在我担任本科生研究助理、研究生和博士后期间，我对滥用药物如何改变大脑突触产生了浓厚的兴趣。我有幸与像博士这样的伟大科学家一起工作。肯·麦基（Ken Mackie）和大卫·洛文格（David Lovinger）等人教会了我宝贵的技能，不仅包括研究技巧，还包括参与假设驱动的科学。这些导师教会我提出许多问题，设计仔细而有针对性的实验，并批判性地解释数据。此外，他们为我提供了很多机会来指导我所从事的工作，让我有时会失败并从失败中学习。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。在该奖项的指导阶段，我将得到校内临床和生物学研究部门的支持，并接受 Lovinger 博士的指导。我有许多高素质的同事，他们随时可以教我完成此处介绍的工作所需的新技术。通过该项目的指导阶段，我将学习并精通新技能，例如快速扫描循环伏安法、乙醇给药范例以及将药物注入脑组织。我还将培养我接受过的有限培训的技能，例如立体定位手术和光遗传学协议。此外，在 NIAAA，我可以获得高质量的研究设备和用品，这将使我能够完成指导阶段将要完成的工作。在整个指导和过渡阶段，我将获得额外的指导经验和技能，这将使我能够在未来独立监督自己的研究实验室。此外，我与酒精研究领域的许多专家保持着密切的联系，从他们身上我可以学到很多东西，并成为这个研究社区的完全整合的成员。我相信，凭借 Lovinger 博士的主要指导、精选同事委员会的额外指导以及 NIAAA 的机构环境，我将能够实现成为一名完全独立的神经科学家的目标。