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

项目总结/摘要 频繁的酗酒与许多负面后果有关，包括增加 发展对乙醇的依赖因此，识别神经元机制是至关重要的， 调节狂饮，因为这些知识将为新的药物治疗提供见解， 防止这种危险的行为和过渡到乙醇依赖。相当多的关注 乙醇的强化作用以及这些作用如何刺激乙醇的摄入。有强有力 有证据表明，乙醇也带来了令人厌恶的影响，这些影响，因为他们显然是剂量 相关的，可以作为一种威慑过度消费。一项临床前行为测定， 乙醇是条件性味觉厌恶（CTA）的发展。当一种口味与一种治疗相结合时 这会产生令人厌恶的内部症状，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，对乙醇的厌恶作用的敏感性与 自愿摄入乙醇重要的是，最近的数据表明，小鼠选择性繁殖，以实现高血 酒精浓度（BECs），而暴饮暴食表现出降低的敏感性， 乙醇，而不改变对乙醇的增强性能的敏感性。因此，酒精饮料在 这些小鼠可能是由于对乙醇的厌恶作用的敏感性降低而被驱使的。因为神经回路 乙醇的负面影响的基础仍然知之甚少，我们建议将联合收割机 化学遗传学、分子学和行为学工具来表征调节厌恶反应的神经回路 酒精和酒精的狂饮。根据以前的研究和令人信服的试点数据，我们将 测试脑干去甲肾上腺素（NE）核，特别是蓝斑（LC）和 A2区（孤束尾核; NTS），在酗酒和服务期间被激活 作为一种保护机制，通过促进厌恶反应来“打破”乙醇饮用。具体目标1将使用 设计者受体仅由设计者药物激活（DREADD）病毒载体研究NE的作用 LC到头内侧被盖核（RMTg）的回路在乙醇诱导的CTA调制中的作用 和酗酒一样的酒精消耗，目标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）在乙醇诱导的CTA调制中的作用， 酗酒般的酒精消费目的3将采用免疫组化和实时荧光PCR方法检测 假设暴饮暴食式饮酒会增加LC和A2中的NE信号传导，并且这种信号传导 在反复的暴饮暴食后，大脑会变得迟钝，这种机制可能有助于 过渡到依赖。由于乙醇的负面影响的机制还不清楚， 了解，和调查中的NE电路的作用从来没有研究关于 神经生物学反应的乙醇，提出的研究是非常新颖和创新的。

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.