Endocannabinoid influence in alcohol dependence-related HPA axis dysregulation

内源性大麻素对酒精依赖相关 HPA 轴失调的影响

• 批准号: 9191289
• 负责人: Sarah A. Laredo
• 金额: $ 0.84万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191289
• 关键词: 2-arachidonylglycerol; ABHD6 gene; AM 251; Abstinence; Acute; Adrenal Glands; Affect; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Analytical Chemistry; Animals; Area; Behavior; Behavior Therapy; Binding; Biological Assay; Brain region; CNR1 gene; Cannabinoids; Catabolism; Chronic; Cognitive; Corticotropin; Data; Data Collection; Dependence; Disease; Education; Endocannabinoids; Enzyme-Linked Immunosorbent Assay; Enzymes; Ethanol; Fatty Acids; Fellowship; Glycerol; Goals; Heavy Drinking; Hydrolase; Hypothalamic structure; Individual; Institutes; Institution; Interneurons; Investigation; Laboratories; Learning; Ligands; Link; Lipase; Lipids; Medial; Mediating; Mental Health; Mental disorders; Microdialysis; Peripheral Nervous System; Pharmacological Treatment; Pituitary Gland; Plasma; Population; Postdoctoral Fellow; Prefrontal Cortex; Process; Proteins; Rattus; Regulation; Relapse; Research Institute; Resources; Risk; Role; Self Administration; Serine Hydrolase; Signal Transduction; Stress; Technical Expertise; Techniques; Time; Training; Withdrawal; activity-based protein profiling; acute stress; alcohol abstinence; alcohol relapse; alcohol research; alcohol use disorder; anandamide; anxiety-like behavior; biological adaptation to stress; cannabinoid receptor; cognitive function; collaborative environment; design; endogenous cannabinoid system; enzyme activity; experience; gamma-Aminobutyric Acid; high risk; high standard; hypothalamic-pituitary-adrenal axis; in vivo; indexing; interest; interstitial; liquid chromatography mass spectrometry; meetings; neurochemistry; neurotransmitter release; new therapeutic target; novel; physical conditioning; receptor; receptor binding; receptor coupling; research and development; research study; responsible research conduct; restraint; restraint stress; targeted treatment; training opportunity; vapor

Project Summary The current project supports the postdoctoral fellow applicant in expanding her technical skills to include in vivo investigations of neurochemical processes during behavioral and pharmacological treatment, as well as ex vivo examination of enzyme activity and receptor coupling. In addition, the applicant will learn analytical chemistry techniques with which to examine these data, including liquid chromatography mass spectrometry (LC-MS), activity based protein profiling (ABPP) and [35S]GTPγS binding. These techniques will be employed in the current proposal, which investigates the effects of stress and protracted alcohol withdrawal on endocannabinoid (eCB) regulation of hypothalamic-pituitary-adrenal (HPA) axis activity and voluntary alcohol consumption. Aim 1 of this proposal targets dysregulation of the eCB system (including catabolizing enzymes and cannabinoid 1 receptor (CB1) binding), GABA release, and HPA responsivity following chronic intermittent ethanol (CIE) vapor exposure. The region of interest in the current studies is the prelimbic (PrL) division of the medial prefrontal cortex since this area exerts top-down control over HPA activity and cognitive behaviors associated with imminent relapse. The second Aim is designed to examine how eCB activity in the PrL affects voluntary alcohol consumption in protracted alcohol withdrawal. The proposed studies will require the applicant to receive extensive methodological training in neurochemical data collection, analysis and interpretation and will support the applicant's overall goal of examining novel therapeutic targets for the treatment of psychiatric illness and alcohol addiction. Furthermore, the applicant's sponsor is highly regarded and successful in the alcohol and eCB fields, and possesses both the fiscal and material resources to support the applicant during the fellowship period. The Scripps Research Institute (TSRI) is an ideal institution for providing additional training and resources to the applicant outside of the laboratory. Departmental meetings as well as meetings of TSRI's Alcohol Research Center (ARC) impart invaluable experience towards participation in research and development goals of the institute, and towards networking in an interdisciplinary and collaborative environment. Additionally, TSRI is committed to promoting the highest standards of the responsible conduct of research, and has partnered with UC San Diego to provide several opportunities towards furthering the applicant's education in these fields. Through these exemplary training opportunities at TSRI, the applicant will be well supported to examine the novel studies proposed in this application.

项目摘要 目前的项目支持博士后研究员将她的技术技能扩展到 包括对行为和药物治疗期间神经化学过程的活体研究，如 以及酶活性和受体偶联的体外检测。此外，申请者还将学习 用于检查这些数据的分析化学技术，包括液相色谱质谱 光谱(LC-MS)、基于活性的蛋白质谱(ABPP)和[35S]GTPγS结合。这些技术将 在目前的提案中使用，该提案调查压力和长期戒酒的影响 内源性大麻素(ECB)对下丘脑-垂体-肾上腺(HPA)轴活动的调节及自愿性 饮酒。该提案的目标1针对的是欧洲央行系统的失调(包括分解 酶和大麻素1受体(CB1结合)、GABA释放和HPA反应性 间歇性乙醇(CIE)蒸气暴露。当前研究中感兴趣的领域是初步(PRL) 内侧前额叶皮质的分裂，因为该区域自上而下地控制HPA的活动和认知 与即将复发相关的行为。第二个目标是检查欧洲央行在欧洲央行的活动 催乳素影响稽延性戒酒的自愿性饮酒。拟议的研究将需要 申请人接受神经化学数据收集、分析和分析方面的广泛方法学培训 并将支持申请人审查新的治疗靶点的总体目标 治疗精神疾病和酒精成瘾。此外，申请人的赞助人受到高度评价 在酒类和欧洲央行领域取得成功，并拥有财力和物力支持 研究金期间的申请人。斯克里普斯研究所(TSRI)是一个理想的 在实验室之外为申请人提供额外的培训和资源。部门会议作为 以及TSRI酒精研究中心(ARC)的会议为参与提供了宝贵的经验 在研究所的研究和发展目标方面，以及在跨学科和 协作环境。此外，TSRI致力于推动最高标准的 负责任的研究，并与加州大学圣地亚哥分校合作，提供几个机会 以进一步加强申请人在这些领域的教育。通过这些模范的培训机会， TSRI，申请人将得到很好的支持，以审查本申请中提出的新颖研究。