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）：背纹状体MU阿片受体功能和酒精使用项目摘要：此处提出的提案旨在更好地理解MU阿片类受体（MOR）在背纹状体在从酒精使用过渡到滥用的过渡中的作用。莫尔斯可能发挥重要作用的一个大脑区域是背纹状体，这是从目标定向到习惯药的过渡中的关键结构，包括酒精使用是少数有效的酒精使用药理学治疗方法之一，是阿片类药物受体拮抗剂。此外，缺乏MOR的转基因小鼠似乎会发现酒精厌恶。另一方面，酒精的长期消费可能会改变背纹状体中MOR的水平和功能耦合。我的初步数据表明，长期的酒精暴露破坏了背纹状体中正常的长期突触可塑性。因此，在该大脑区域中，酒精消耗与MOR的功能之间似乎存在相互作用，这可能是从吸毒使用到成瘾的过渡。我在这里假设乙醇暴露会改变特定纹状体突触下的MOR介导的可塑性，并且在这些同一突触下操纵MOR功能将改变乙醇的完整行为。为了检验这些假设，我提出了以下三个特定目标。 1。在特定目标1中，我将确定酒精介导的背纹状体依赖性纹状体输入的长期可塑性的破坏是全球性的还是特定于突触的。我将使用光遗传学和药理学来专门探测不同的纹状体输入，并确定哪些对MOR敏感的纹状体输入以及慢性酒精是否会破坏这种可塑性。这将提供有关什么的线索 对背纹状体的输入类型（执行，联想，感觉等）会因酒精的使用而改变，并提供有关酒精对行为影响的MOR调节作用的新假设。 2。在特定目标2中，我将确定酒精对多巴胺能信号传导调节的影响。尚不清楚MOR如何调节背纹状体多巴胺的释放以及该调节是否因酒精暴露而改变。此外，背纹状体中多巴胺能神经适应于长时间的酒精暴露可能是由于正常，依赖性过程的破坏而导致的。在背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，在此目的中，我特别解决了胆碱能中间神经元的MORS是MOR对多巴胺释放作用的关键组成部分的假设，并且乙醇破坏了这种正常的MOR调节多巴胺释放。 3。在我的最终目标中，我将在药理和遗传上操纵背纹状体功能，并观察这些改变对饮酒的影响。我将检验以下假设：MOR背侧纹状体激活会导致饮酒量增加，相反，MOR抑制作用会减少乙醇的消耗。此外，我将使用转基因小鼠从特定的神经元类型中消除MOR的表达，并观察这些遗传改性的小鼠是否仍然食用酒精。这些实验将揭示背侧纹状体中的MOR，更具体地说是在不同的细胞类型中，控制酒精的束缚行为。在我担任本科研究助理，研究生和博士后研究员的过程中，我对虐待药物如何变化大脑的突触有浓厚的兴趣。我有幸与伟大的科学家（例如Drs）合作。肯·麦基（Ken Mackie）和戴维·洛夫（David Lovinger）等人教给我宝贵的技能，不仅是研究技巧，而且还从事假设驱动的科学。这些导师教会我提出许多问题，设计谨慎而专注的实验，并批判性地解释数据。此外，他们为我提供了许多指导我执行工作过程的机会，使我有时会失败并从这些失败中学习。由于这些个人和我的许多其他同事的指导，我是一个更好的科学家。在该奖项的指导阶段，我将得到壁内临床和生物学研究部的支持，并将在Lovinger博士的指导下。我有许多高素质的同事，可以很容易地教我完成此处介绍的工作所需的新技术。由于该项目的指导阶段，我将学习并精通新技能，例如快速扫描的循环伏安法，乙醇给药范式以及将药物输注到脑组织中。我还将开发我接受过有限培训的技能，例如立体定位手术和光遗传学方案。此外，在NIAAA，我可以使用高质量的研究设备和用品，这将使我能够实现在指导阶段所做的工作。在整个指导和过渡阶段，我将获得更多的指导经验和技能，使我将来能够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，我可以从中学到很多东西，并成为该研究社区的完全融合成员。我有信心，通过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，我将能够实现成为完全独立的神经科学家的目标。