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

摘要 频繁的狂饮，以及整个生命周期中常见的酒精（乙醇）消费模式， 与许多不良后果有关。特别令人担忧的是，经常酗酒 显著增加了个体发展乙醇依赖的风险。因此，这是一个非常重要的目标， 以确定神经机制，调节酗酒，因为这样的知识将提供深入了解新的 药物治疗，以帮助遏制狂饮，这反过来可能会降低风险的进展， 更严重的酒精使用障碍（AUDs）。针对AUD神经生物学的研究集中在 相当多的关注乙醇的强化作用，以及这些作用如何激发酗酒样乙醇 摄入有趣的是，越来越多的证据表明，乙醇也会带来令人厌恶的影响， 由于这些影响显然与剂量有关，因此可对过度消费起到威慑作用。因为 乙醇的负面影响背后的神经回路仍然知之甚少，在上一个资助期， 开始描述调节乙醇厌恶反应的神经机制及其作用 在调节酒精摄入方面的作用。我们发现，酗酒式的酒精饮用会增加 A2（孤束尾核; NTS）和A6（蓝斑; LC）脑干区域中的神经元， 去甲肾上腺素（NE）的两个主要来源，将传入投射发送到许多大脑结构 调节动机行为的神经系统。有趣的是，我们发现NE+回路的化学发生激活 从LC到头内侧被盖核（RMTg）或A2到臂旁外侧核（PBN）， 与调节乙醇的厌恶性质有关的靶区域， 酒精摄入过量的老鼠。此外，激活NE+ LC-RMTg回路， 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 指导性假设是这些NE+回路的激活触发了保护机制来“破坏”乙醇 通过促进对乙醇的厌恶反应来摄入乙醇。最近，我们观察到NE电路产生的LC 和A2，直接支配腹侧被盖区（VTA），这是一个对调节奖赏和兴奋的关键大脑区域。 和厌恶令人惊讶的是，几乎没有研究NE信号在VTA中的作用。 调节乙醇摄入或乙醇的厌恶性质。拟议的实验逻辑上来自于 最初的赠款，但将大大提高我们的了解新的机制正在调查1） 揭示了新的NE+电路，调节酗酒样乙醇摄入量和乙醇的厌恶性质，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 在RMTg，PBN和VTA中的特定神经元群体上的表达，这些神经元是由反复的狂欢周期引起的。 比如乙醇摄入量由于研究中的机制和NE回路很少受到关注， 关于乙醇的神经生物学反应，所提出的研究是高度新颖和创新的。

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.