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

摘要 经常酗酒，以及一生中普遍存在的酒精(乙醇)消费模式， 与许多不良后果有关。尤其令人担忧的是，经常酗酒 显著增加个人患酒精依赖的风险。因此，这是一个非常重要的目标。 识别调节酗酒的神经元机制将为我们提供对新奇的 药物治疗有助于遏制酗酒，进而可能降低进展为 更严重的酒精使用障碍(AUD)。针对AUDS的神经生物学的研究已经集中在 相当重视乙醇的强化作用，以及这些作用如何激发类似酒精的暴饮暴食 入口处。有趣的是，有越来越多的证据表明，乙醇也会产生不良影响，而这些 效果，因为它们明显与剂量有关，可以起到威慑过度消费的作用。因为 乙醇的不良反应背后的神经回路仍然知之甚少，在上一个资金阶段，我们 开始描述调节酒精厌恶反应的神经元机制及其作用 在调节像狂欢一样的乙醇消费方面。我们发现，像酗酒一样的饮酒会增加脑细胞的活性 脑干区A2(孤束尾侧核；NTS)和A6(蓝斑；LC)神经元； 去甲肾上腺素(NE)的两个主要来源，它们向许多大脑结构发送传入投射 来调节有动机的行为。有趣的是，我们发现NE+环路的化学激活 从LC至被盖内侧核(RMTg)或A2至臂旁外侧核(PBN)， 与调节乙醇的厌恶特性有关的靶区，显著钝化 老鼠暴饮暴食的酒精摄入。此外，激活NE+LCRMTG回路可诱导无条件厌恶 小鼠的行为，并沉默这一途径减弱乙醇诱导的条件性味觉厌恶(CTA)。我们的 指导性假设是，这些NE+环路的激活触发了一种保护机制，以“分解”乙醇 通过促进对乙醇的厌恶反应来摄取。最近，我们观察到从LC产生的NE回路 和A2，直接支配腹侧被盖区(VTA)，这是大脑中调节两种奖赏的关键区域 和厌恶感。令人惊讶的是，几乎没有关于NE信号在VTA中的作用的研究 乙醇摄入量的调节或乙醇的厌恶特性。从逻辑上讲，拟议的实验来自 原始拨款，但将极大地促进我们对正在调查的新机制的理解1) 揭示了新的NE+回路，它调节了酒精的暴饮式摄取和乙醇的厌恶特性，2) 确定参与的肾上腺素能受体(AR)，以及3)确定AR中的神经可塑性变化 反复暴饮暴食引起的RMTg、PBN和VTA内特定神经元群体的表达 比如酒精摄入量。由于正在研究的机制和NE电路很少受到关注，因此 在乙醇的神经生物学反应方面，建议的研究具有很高的新颖性和创新性。

Abstract Frequent binge drinking, and common pattern of alcohol (ethanol) consumption across the lifespan, has been linked to numerous adverse consequences. Particularly concerning is the fact that regular binge drinking significantly increases an individual’s risk of developing ethanol dependence. Thus, it is a highly significant goal to identify neuronal mechanisms that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments to help curb binge drinking and which in turn may reduce the risk of progressing to more serious forms of alcohol use disorders (AUDs). Research aimed at the neurobiology of AUDs has focused considerable attention to the reinforcing effects of ethanol and how these effects motivate binge-like ethanol intake. Interestingly there is accumulating evidence that ethanol also entails aversive effects and that these effects, because they are clearly dose related, can act as a deterrent to overconsumption. Because the neurocircuitry underlying the aversive effects of ethanol is still poorly understood, in the last funding period we began to characterize the neuronal mechanisms that modulate the aversive reactions to ethanol and their role in modulating binge-like ethanol consumption. We found that binge-like ethanol drinking increases the activity of neurons in the A2 (caudal nucleus of the solitary tract; NTS) and A6 (locus coeruleus; LC) brainstem regions, two of the primary sources of norepinephrine (NE) that send afferent projections to numerous brain structures that modulate motivated behaviors. Interestingly, we discovered that chemogenetic activation of NE+ circuits from the LC to the rostromedial tegmental nucleus (RMTg) or the A2 to the lateral parabrachial nucleus (PBN), target regions that have been implicated in modulating the aversive properties of ethanol, significantly blunted binge-like ethanol intake in mice. Further, activating the NE+ LC  RMTg circuit induced unconditioned aversive behaviors in mice, and silencing this pathway attenuated ethanol-induced conditioned taste aversion (CTA). Our guiding hypothesis is that activation of these NE+ circuits trigger a protective mechanism to “break” ethanol intake by promoting aversive responses to ethanol. More recently, we observed NE circuits arising from the LC and A2 that directly innervate the ventral tegmental area (VTA), a brain region critical for modulating both reward and aversion. Surprisingly, there has been almost no investigation into the role of NE signaling in the VTA in the modulation of ethanol intake or the aversive properties of ethanol. Proposed experiments logically flow from the original grant but will significantly advance our understanding of the novel mechanisms under investigation by 1) revealing novel NE+ circuits that modulate binge-like ethanol intake and the aversive properties of ethanol, 2) identifying the adrenergic receptors (AR) that are involved, and 3) identifying neuroplastic changes in AR expression on specific populations of neurons in RMTg, PBN, and VTA resulting from repeated cycles of binge- like ethanol intake. As the mechanisms and NE circuits under investigation have received little attention with respect to neurobiological response to ethanol, the proposed studies are highly novel and innovative.