The role of brainstem norepinephrine in binge alcohol drinking and taste aversion

脑干去甲肾上腺素在酗酒和味觉厌恶中的作用

• 批准号: 9883691
• 负责人: TODD E. THIELE
• 金额: $ 34.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883691
• 关键词: Alcohol consumption; Alcohol dependence; Alcohols; Attention; Behavioral; Behavioral Assay; Blood; Brain; Brain Stem; Cell Nucleus; Clozapine; Dangerous Behavior; Data; Dependence; Development; Dopamine-beta-monooxygenase; Dose; Emetics; Ethanol; Ethanol dependence; Exhibits; Exposure to; FOS gene; Female; G alpha q Protein; Grant; Health; Heart Diseases; Heavy Drinking; Hypertension; Immunohistochemistry; Infusion procedures; Ingestion; Investigation; Knowledge; Lateral; Link; Lithium Chloride; Messenger RNA; Molecular; Mood Disorders; Mus; Neurobiology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nucleus solitarius; Oxides; Pathway interactions; Pharmacologic Substance; Property; Proteins; Reaction; Recombinant adeno-associated virus (rAAV); Recording of previous events; Research; Risk; Rodent; Role; Signal Transduction; Site; Source; Structure; Symptoms; Taste Perception; Taste aversion; Testing; Time; Tyrosine 3-Monooxygenase; Viral Vector; alcohol effect; alcohol response; alcohol sensitivity; base; binge drinking; designer receptors exclusively activated by designer drugs; drinking; immunoreactivity; innovation; insight; locus ceruleus structure; male; motivated behavior; neural circuit; noradrenaline transporter; novel; parabrachial nucleus; pre-clinical; prevent; response; tool

Project Summary/Abstract Frequent binge drinking has been linked to numerous negative consequences, include and increased risk of developing ethanol dependence. Thus, it is of paramount importance to identify neuronal mechanisms that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior and the transition to ethanol dependence. Considerable attention has been paid to the reinforcing effects of ethanol and how these effects motivate ethanol intake. There is strong evidence that ethanol also entails aversive effects and that these effects, because they are clearly dose related, can act as a deterrent to overconsumption. One pre-clinical behavioral assay for the aversive effects of ethanol is the development of a conditioned taste aversion (CTA). When a taste is paired with a treatment which produces aversive internal symptoms, a strong aversion to the taste develops. Studies comparing different rodent strains suggest a link between sensitivity to the aversive effects of ethanol and the propensity to voluntarily ingest ethanol. Importantly, recent data show that mice selectively bred to achieve high blood ethanol concentrations (BECs) while binge drinking exhibit reduced sensitivity to the aversive properties of ethanol without alterations in sensitivity to ethanol’s reinforcing properties. Thus, binge-like ethanol drinking in these mice may be driven by reduced sensitivity to ethanol’s aversive effects. Because the neurocircuitry underlying the aversive effects of ethanol is still poorly understood, we propose to combine cutting-edged chemogenetic, molecular, and behavioral tools to characterize the neurocircuitry modulating aversive reactions to ethanol and binge-like ethanol consumption. Based on previous studies and compelling pilot data, we will test the novel hypothesis that brainstem norepinephrine (NE) nuclei, specifically the locus coeruleus (LC) and A2 region (caudal nucleus of the solitary tract; NTS), are activated during binge-like ethanol drinking and serve as protective mechanisms to “break” ethanol drinking by promoting aversive responses. Specific Aim 1 will use Designer Receptors Exclusively Activated by Designer Drugs (DREADD) viral vectors to study the role of a NE circuit from the LC to the rostromedial tegmental nucleus (RMTg) in the modulation of ethanol-induced CTA and binge-like ethanol consumption, and Aim 2 will use DREADD viral vectors to study the role of a NE circuit from the A2 region to the lateral parabrachial nucleus (PBN) in the modulation of ethanol-induced CTA and binge-like ethanol consumption. Aim 3 will use immunohistochemistry and real-time PCR approaches to test the hypothesis that binge-like ethanol drinking increases NE signaling in the LC and A2, and that this signaling will become blunted after repeated binge-like drinking episodes, a mechanism that may contribute to the transition to dependence. As the mechanisms underlying the aversive effects of ethanol are not well understood, and the roles of the NE circuits under investigation have never been studies with respect to neurobiological response to ethanol, the proposed studies are highly novel and innovative.

项目概要/摘要 经常暴饮暴食会带来许多负面后果，包括增加酗酒的风险 发展乙醇依赖。因此，确定神经元机制至关重要 调节酗酒，因为这些知识将提供对新型药物治疗的深入了解，这些治疗将 防止这种危险行为和向乙醇依赖的转变。引起了相当大的关注 人们关注乙醇的增强作用以及这些作用如何刺激乙醇的摄入。有很强的 有证据表明，乙醇也会产生厌恶效应，并且这些效应，因为它们显然与剂量有关 相关的，可以起到遏制过度消费的作用。一种针对不良反应的临床前行为测定 乙醇是条件性味觉厌恶（CTA）的发展。当味道与治疗相结合时 这会产生厌恶的内部症状，对味道产生强烈的厌恶。研究比较 不同的啮齿动物品系表明对乙醇厌恶作用的敏感性与倾向之间存在联系 自愿摄入乙醇。重要的是，最近的数据表明，选择性繁殖的小鼠可以达到高血 酗酒时的乙醇浓度（BEC）表现出对令人厌恶的特性的敏感性降低 乙醇而不改变对乙醇增强特性的敏感性。因此，狂饮乙醇 这些小鼠可能是由于对乙醇厌恶作用的敏感性降低而驱动的。因为神经回路 乙醇潜在的厌恶作用仍然知之甚少，我们建议结合尖端技术 化学遗传学、分子和行为工具来表征调节厌恶反应的神经回路 乙醇和暴饮暴食式的乙醇消费。根据之前的研究和令人信服的试点数据，我们将 检验新的假设，即脑干去甲肾上腺素 (NE) 核，特别是蓝斑 (LC) 和 A2 区域（孤束尾核；NTS）在狂饮乙醇时被激活并发挥作用 作为通过促进厌恶反应来“打破”乙醇饮酒的保护机制。具体目标 1 将使用 由设计药物 (DREADD) 病毒载体独家激活的设计受体，用于研究 NE 的作用 乙醇诱导的 CTA 调节中从 LC 到头内侧被盖核 (RMTg) 的电路 和暴饮暴食式的乙醇消耗，Aim 2 将使用 DREADD 病毒载体来研究 NE 回路的作用 在乙醇诱导的 CTA 调节中从 A2 区域到臂旁核外侧核 (PBN) 暴饮暴食般的乙醇消耗。目标3将使用免疫组织化学和实时PCR方法进行测试 假设暴饮暴食乙醇会增加 LC 和 A2 中的 NE 信号传导，并且这种信号传导 在反复的暴饮暴食之后，大脑的功能会变得迟钝，这种机制可能会导致 过渡到依赖。由于乙醇的厌恶作用背后的机制尚不明确 理解，并且所研究的 NE 电路的作用从未被研究过 对乙醇的神经生物学反应，拟议的研究非常新颖和创新。