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.

项目概要 不幸的是，尽管人数很少，但酒精使用障碍 (AUD) 影响着美国约 1600 万人。 目前可用的治疗方法，复发率非常高。压力是复发的常见诱因； 因此，它是 AUD 治疗的主要目标。该提案将研究压力的综合影响。 酒精使用对边缘系统神经回路的影响，边缘系统是涉及情绪的主要结构组 该提案的第一个具体目标是测试压力和乙醇相互作用的假设。 促进终纹床核 (BNST) 中的 β2-肾上腺素能受体 (b2-AR) 信号传导 增加自愿乙醇摄入量将使用全细胞膜片钳电生理学进行测试， 第二个目的是测试 BNST 神经元的化学遗传学操作和荧光原位杂交。 假设靶向 BNST 中糖皮质激素受体 (GR) 介导的信号传导将减轻 b2-AR 这将在压力和乙醇摄入后发生依赖性行为和神经回路变化。 通过染色质免疫沉淀 (ChIP)、电生理学和药理学操作 GR. 与国家酒精滥用和酒精中毒研究所 (NIAAA) 的使命保持一致， 该研究计划将通过识别神经回路来调查酒精对健康和福祉的影响 最终得出这些结果的结果是暴露于压力和酒精的小鼠与幼稚小鼠之间的差异。 研究将有助于制定与压力相关的酒精使用障碍的预防和治疗方法。