Role of Dynorphin/Kappa Activity Within the Extended Amygdala in Binge Ethanol Drinking

扩展杏仁核内的强啡肽/卡帕活性在酗酒中的作用

• 批准号: 9815305
• 负责人: Harold L Haun
• 金额: $ 4.19万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815305
• 关键词: Accidental Injury; Address; Agonist; Alcohol consumption; Alcohols; Amygdaloid structure; Attenuated; Behavior; Biosensor; Blood; Brain; Brain region; Calcium; Cells; Dangerousness; Data; Dependence; Development; Dynorphins; Economics; Ethanol; Fellowship; Female; Fiber; Goals; Health; Heavy Drinking; Impairment; Individual; Injections; Internal Ribosome Entry Site; Intoxication; Legal; Literature; Measurement; Measures; Mediating; Microinjections; Modeling; Motivation; Mus; National Research Service Awards; Neurons; Neuropeptide Receptor; Neuropeptides; Pathway interactions; Pattern; Pharmacology; Photometry; Pre-Clinical Model; Regulation; Research; Research Personnel; Research Project Grants; Retroviridae; Risk; Role; Signal Transduction; Specificity; Stress; Structure; Structure of terminal stria nuclei of preoptic region; System; Technical Expertise; Techniques; Testing; Time; Training; Transgenic Organisms; Violence; Viral; Woman; Work; alcohol behavior; alcohol effect; alcohol relapse; alcohol research; alcohol use disorder; binge drinking; brain circuitry; career; design; designer receptors exclusively activated by designer drugs; drinking; dysphoria; experience; in vivo; kappa opioid receptors; male; men; motivated behavior; mouse model; neurochemistry; neuromechanism; overdose risk; preclinical study; prodynorphin; skills; social; therapeutic development

PROJECT SUMMARY Excessive alcohol (ethanol) intake in a binge-like fashion has emerged as a significant health risk in both males and females. Binge drinking is defined as a pattern of drinking that leads to blood ethanol concentrations (BEC) above legal limit of intoxication within a relatively short period of time. Among several neurochemical and neuropeptide systems implicated in binge drinking, recent findings have implicated a role for the dynorphin/kappa opioid receptor (DYN/KOR) system. Recently we showed that systemic administration of a KOR agonist increased while a KOR antagonist decreased ethanol intake in a mouse model of binge drinking. Further, using a prodynorphin-IRES-Cre mouse line to target an inhibitory (hM4Di) DREADD in DYN-containing (DYN+) neurons in the central amygdala (CeA), we showed chemogenetic inhibition of these neurons (via systemic CNO injection) reduced binge drinking. The bed nucleus of the stria terminalis (BNST) is a functionally important target of the CeA and both structures are implicated in motivated behavior, including ethanol drinking. Targeted anterograde viral tracing of DYN+ neurons in the CeA showed dense terminal fields within the BNST. This, along with relevant pilot data suggest that DYN/KOR activity within the CeA-BNST pathway is involved in binge drinking. Thus, the overall hypothesis to be tested in this project is that increased DYN/KOR activity within the CeA-BNST pathway contributes to binge-like ethanol consumption. The proposed research plan will employ a comprehensive approach that entails using pharmacological, chemogenetic, and fiber photometry techniques to examine the contribution of DYN/KOR activity within the CeA-BNST pathway to binge drinking in male and female mice. Studies in Aim 1 will examine the effects of pharmacologically manipulating KOR in the BNST on binge ethanol drinking in male and female C57BL/6J mice. Studies in Aim 2 will utilize a targeted chemogenetic approach to examine the effects of ‘silencing’ and activating DYN+ neurons in the CeA-BNST pathway on binge ethanol drinking in male and female mice. Aim 3 will utilize fiber photometry to selectively measure activity in DYN+ neurons within the CeA-BNST pathway while mice are drinking in the binge ethanol drinking model. Results from this project will advance our understanding of the role of the DYN/KOR system within extended amygdala (CeA-BNST pathway) in binge ethanol drinking. Further, this research plan will serve as an ideal platform for my comprehensive training plan that is designed to provide me with the opportunity to acquire and apply new technical skills that will enhance my goal of pursuing a research career in the alcohol field.

项目摘要 过量的酒精（乙醇）摄入量在一个狂欢般的时尚已成为一个重大的健康风险，在这两个男性 和女性。酗酒是指导致血液中乙醇浓度（BEC）升高的饮酒模式 在相对较短的时间内超过法律的醉酒限度。在几种神经化学物质和 神经肽系统参与酗酒，最近的研究结果表明，强啡肽/κ 阿片受体（DYN/KOR）系统。最近，我们发现全身给予KOR激动剂， 增加，而KOR拮抗剂减少酒精摄入量的小鼠模型的酗酒。此外，使用 靶向含DYN（DYN+）中的抑制性（hM 4Di）DREADD的前强啡肽-IRES-Cre小鼠系 在中央杏仁核（CeA）的神经元，我们表现出这些神经元的化学发生抑制（通过全身CNO 减少酗酒。终纹床核（BNST）是一个重要的功能靶点 这两种结构都与动机性行为有关，包括饮酒。针对性 在CeA中的DYN+神经元的顺行病毒追踪显示在BNST内的密集终末野。这个，沿着 相关的初步数据表明，CeA-BNST通路中的DYN/KOR活性与暴食有关， 喝酒因此，在本项目中要检验的总体假设是， CeA-BNST途径有助于酗酒样的乙醇消耗。拟议的研究计划将采用 一种综合方法，需要使用药理学、化学发生学和纤维光度测定技术， 检查CeA-BNST通路中DYN/KOR活性对男性酗酒的贡献， 雌性老鼠目标1中的研究将检查在BNST中操纵KOR的干扰对 在雄性和雌性C57 BL/6 J小鼠中的酗酒。目标2中的研究将利用靶向化学遗传学 研究CeA-BNST通路中“沉默”和激活DYN+神经元对狂欢的影响的方法 雄性和雌性小鼠的酒精摄入量。AIM 3将利用纤维光度法选择性地测量 在小鼠饮酒过量乙醇饮酒模型中，CeA-BNST通路内的DYN+神经元。 从这个项目的结果将促进我们的DYN/KOR系统的作用的理解， 杏仁核（CeA-BNST途径）在酒精狂饮中的作用。此外，这项研究计划将作为一个理想 我的全面培训计划的平台，旨在为我提供机会， 获得和应用新的技术技能，这将提高我追求研究事业的目标， 酒精领域