Novel role of beta2-adrenergic receptor signaling in vBNST CRF-mediated stress-induced ethanol intake

β2-肾上腺素能受体信号在 vBNST CRF 介导的应激诱导的乙醇摄入中的新作用

• 批准号: 10005021
• 负责人: Angela E Snyder
• 金额: $ 3.23万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005021
• 关键词: AR gene; Abstinence; Address; Adrenergic Receptor; Affect; Alcohol consumption; Alcohols; Anterior; Behavior; Behavioral; Brain; Brain region; Cells; Chronic; Cocaine; Corticotropin-Releasing Hormone; Data; Disease; Dorsal; Drug Modulation; Drug Targeting; Electrophysiology (science); Emotional; Ethanol; Evaluation; Fluorescent in Situ Hybridization; Future; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Group Structure; Health; Intake; Knowledge; Limbic System; Measures; Mediating; Mission; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurosciences; Personal Satisfaction; Pharmacological Treatment; Pharmacology; Prevention; Promoter Regions; Public Health; Quantitative Reverse Transcriptase PCR; Receptor Signaling; Relapse; Research; Research Proposals; Response Elements; Rodent Model; Role; Signal Transduction; Signaling Molecule; Site; Stress; Structure of terminal stria nuclei of preoptic region; Substance Use Disorder; Techniques; Testing; Training; United States; Up-Regulation; acute stress; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol use disorder; base; behavior observation; behavioral response; behavioral study; beta-adrenergic receptor; brain circuitry; career; chromatin immunoprecipitation; drinking; drug seeking behavior; enhancing factor; experimental study; glutamatergic signaling; neural circuit; neurotransmission; noradrenergic; novel; patch clamp; receptor; receptor expression; receptor function; receptor-mediated signaling; stressor; transcription factor; transmission process

PROJECT SUMMARY Alcohol use disorder (AUD) affects about 16 million people in the United States. Unfortunately, despite the few currently-available treatments, the rate of relapse is extraordinarily high. Stress is a common trigger of relapse; therefore it is a prime target for AUD treatment. This proposal will investigate the combined effects of stress and alcohol use on neurocircuitry in the limbic system, the primary group of structures involved in emotional processing. The first specific aim of this proposal is to test the hypothesis that stress and ethanol interact to promote beta2-adrenergic receptor (b2-AR) signaling in the bed nucleus of the stria terminalis (BNST) and increase voluntary ethanol intake. This will be tested using whole-cell patch-clamp electrophysiology, chemogenetic manipulations of BNST neurons, and fluorescent in situ hybridization. The second aim is to test the hypothesis that targeting glucocorticoid receptor (GR)-mediated signaling in the BNST will mitigate b2-AR dependent behavioral and neurocircuit changes following stress and ethanol intake. This will be achieved through chromatin immunoprecipitation (ChIP), electrophysiology, and pharmacological manipulations of the GR. Keeping consistent with the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), this research proposal will investigate alcohol’s effect on health and well-being by identifying neurocircuitry differences between stress and alcohol-exposed mice and naïve mice. Ultimately the findings from these studies will help when developing prevention and treatments for stress-related alcohol use disorder.

项目摘要 在美国，酒精使用障碍（AUD）影响约1600万人。不幸的是，dospite少数 当前可用的治疗方法，继电器的速度非常高。压力是继电器的常见触发因素。 因此，它是AUD治疗的主要目标。该建议将研究压力的综合作用 在边缘系统中的神经记录上使用酒精，这是情感上涉及的主要结构组 加工。该提案的第一个具体目的是检验压力和乙醇相互作用的假设 促进基质末端（BNST）床核的beta2-肾上腺素受体（B2-AR）信号传导和 增加自愿乙醇的摄入量。这将使用全细胞贴片钳电生理学测试， BNST神经元的化学发生操作和荧光原位杂交。第二个目的是测试 靶向BNST中靶向糖皮质激素受体（GR）介导的信号传导的假设将减轻B2-AR 压力和乙醇摄入后，依赖的行为和神经电路变化。这将被实现 通过染色质免疫沉淀（CHIP），电生理学和药物操纵 gr。与国家酗酒和酒精中毒研究所（NIAAA）的任务保持一致， 该研究建议将通过识别神经记录来调查酒精对健康和福祉的影响 压力和暴露于酒精的小鼠与幼稚小鼠之间的差异。最终从这些发现 在开发与压力相关的酒精使用障碍的预防和治疗方法时，研究将有所帮助。