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.

项目摘要/摘要 经常喝酒与许多负面后果有关，包括和增加的风险 发展乙醇依赖性。这是至关重要的，确定神经元机制 调节狂饮饮酒作为这种知识将提供对新型药物治疗的见解 防止这种危险行为以及向乙醇依赖性的过渡。有很大的关注 我们获得了乙醇的增强作用，以及这些作用如何激发乙醇的摄入量。有强大 乙醇也需要厌恶作用和这些作用的证据，因为它们显然是剂量 相关，可以充当过度消费的决定。一种临床前行为测定，以厌恶作用 乙醇是条件味觉厌恶（CTA）的发展。当味道与治疗配对时 会产生厌恶性的内部症状，对味觉发展有很大的厌恶。研究比较 不同的啮齿动物菌株表明，敏感性与乙醇的厌恶作用与诺言之间的联系 重要的是，最近的数据表明，小鼠有选择地育种以获得高血。 乙醇浓度（BEC）时，暴饮暴食降低了对厌恶特性的敏感性 乙醇对乙醇增强特性的敏感性没有改变。那，像狂风一样喝酒 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。因为神经循环 我们建议将乙醇的基础厌恶作用理解不足 化学发生，分子和行为工具，以表征神经记录调节厌恶反应 到乙醇和暴饮暴食的乙醇消耗。根据先前的研究和引人注目的飞行员数据，我们将 检验了脑干去甲肾上腺素（NE）核的新假设，特别是核基因座（LC）和 A2区域（固体道的尾核； NTS）在暴饮暴食时被激活 作为通过促进厌恶反应来“打破”乙醇饮用的受保护机制。具体目标1将使用 设计师药物（Dreadd）病毒载体专门激活的设计师受体研​​究NE的作用 从LC到乙醇诱导的CTA调制中的lc到lo骨的电路 和类似暴饮暴食的乙醇消耗，AIM 2将使用Dreadd病毒向量来研究NE电路的作用 从A2区域到乙醇诱导的CTA和 暴饮暴食的乙醇消耗。 AIM 3将使用免疫组织化学和实时PCR方法进行测试 狂饮样乙醇饮用的假设增加了LC和A2的NE信号传导，并且该信号传导 在反复的暴饮暴食剧集后将变得钝性，这种机制可能有助于 过渡到依赖。由于乙醇的厌恶作用的基础机制不好 正在研究的研究中从未有过有关理解的研究，而正在调查的NE电路的作用从未有过 对乙醇的神经生物学反应，拟议的研究是高度新颖和创新的。