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

项目摘要/摘要 经常酗酒与许多负面后果有关，包括和增加患病风险。 发展对酒精的依赖。因此，确定神经机制是至关重要的。 作为这样的知识，调节酗酒将提供对新的药物治疗的洞察，这些药物治疗将 防止这种危险的行为和向酒精依赖的过渡。已经引起了相当大的关注 人们注意到乙醇的强化作用，以及这些作用是如何刺激乙醇摄入量的。有很强的 有证据表明，乙醇也会产生令人厌恶的影响，而且这些影响，因为它们显然是剂量 相关的，可以起到威慑过度消费的作用。一种临床前行为测试，用于研究阿司匹林的副作用 乙醇是一种条件性味觉厌恶(CTA)的发展。当一种口味与一种治疗搭配时 这会产生令人厌恶的内部症状，对这种味道会产生强烈的厌恶。比较研究 不同的啮齿动物品系表明，对酒精的厌恶作用的敏感性和嗜好之间存在联系。 自愿摄入乙醇。重要的是，最近的数据表明，小鼠有选择地繁殖是为了获得高血液 酗酒时的乙醇浓度(BEC)对酒精的厌恶特性表现出降低的敏感性 乙醇不会改变对乙醇增强特性的敏感性。因此，狂欢式的酒精饮酒 这些小鼠可能是由于对乙醇的厌恶作用的敏感度降低所致。因为神经回路 乙醇的不良影响仍然知之甚少，我们建议将尖端的 化学发生、分子和行为工具来表征调节厌恶反应的神经回路 到乙醇和狂欢的乙醇消费。基于之前的研究和令人信服的试点数据，我们将 检验脑干去甲肾上腺素(NE)核，特别是蓝斑(LC)和 A2区(孤束尾侧核；NTS)，在狂饮酒精时被激活并服务于 作为一种保护机制，通过促进厌恶反应来“打破”酒精饮酒。《特定目标1》将使用 由设计药物(DREADD)病毒载体特异激活的设计受体研究NE的作用 LC至被盖旋转内侧核(RMTg)的回路在乙醇诱导的CTA调制中的作用 和酗酒一样的饮酒，Aim 2将使用DREADD病毒载体来研究NE回路的作用 从A2区到臂旁外侧核(PBN)对乙醇诱导的CTA和 像狂欢一样的乙醇消费。AIM 3将使用免疫组织化学和实时PCR方法来检测 假设酗酒增加了LC和A2中的去甲肾上腺素信号，并且这个信号 在反复暴饮暴饮式饮酒后会变得迟钝，这可能是导致 向依赖过渡。由于乙醇产生厌恶作用的机制还不是很清楚 了解，并且被调查的NE电路的作用从未被研究过 对于乙醇的神经生物学反应，所提出的研究具有很高的新颖性和创新性。

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.