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

基本信息

批准号：
10658145
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658145
关键词：
Adrenergic Receptor Agonist Alcohol consumption Alcohol dependence Alcohols Attention Attenuated Behavior Brain Brain Stem Brain region Cell Nucleus Confocal Microscopy Consumption Dangerous Behavior Data Dependence Dopamine Dose Ethanol Ethanol dependence Female Funding Genetic Glutamates Goals Grant Health Heart Diseases Heavy Drinking Hypertension Immunohistochemistry Individual Intake Investigation Knowledge Lateral Lead Link Longevity Mood Disorders Mus Neurobiology Neuronal Plasticity Neurons Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Nucleus solitarius Outcome Pathway interactions Pattern Pharmacologic Substance Play Population Property Reaction Recording of previous events Reporter Research Rewards Risk Risk Reduction Role Sex Differences Signal Transduction Source Structure Taste aversion Testing Transgenic Mice Ventral Tegmental Area adverse outcome alcohol effect alcohol exposure alcohol response alcohol use disorder antagonist binge drinking drinking experience experimental study innovation insight locus ceruleus structure male motivated behavior neural circuit novel parabrachial nucleus pharmacologic prevent progression risk protein expression receptor expression

项目摘要

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.

抽象的经常喝酒和饮酒（乙醇）在整个生命周期中的常见模式一直是与许多不利后果有关。特别是关于定期暴饮暴食的事实显着增加了个人患乙醇依赖性的风险。那是一个非常重要的目标为了确定调节暴饮暴食的神经元机制将提供对新颖的洞察力药物治疗以帮助遏制暴饮暴食，进而将其降低更严重的酒精使用障碍（AUD）。针对AUDS神经生物学的研究集中非常关注乙醇的增强作用以及这些作用如何激发暴饮暴食般的乙醇进气。有趣的是，有积累的证据表明乙醇也需要厌恶作用，而这些效果，因为它们显然与剂量相关，因此可以充当过度消费的决定。因为乙醇的厌恶作用的基础神经记录仍然很少了解，在最后的资金期间，我们开始表征调节对乙醇及其作用的厌恶反应的神经元机制在调节类似暴饮暴食的乙醇消耗中。我们发现类似暴饮的乙醇饮酒增加了 A2中的神经元（固体道； nts的尾核）和A6（coeruleus; lc）脑干区域，去甲肾上腺素（NE）的两个主要来源，它们将传入项目发送到许多大脑结构这种调节动态行为。有趣的是，我们发现NE+圆圈的化学发生激活从LC到the to the the the the the the temental nucleus（RMTG）或A2，再到外侧甲核（PBN），在调节乙醇的厌恶特性时暗示的目标区域，显着钝化小鼠的暴饮暴食状乙醇摄入量。此外，激活NE+LCRMTG电路引起的无条件厌恶小鼠的行为，并使该途径沉默减弱乙醇引起的条件味觉厌恶（CTA）。我们的指导假设是这些NE+电路的激活触发了受保护的机制“破坏”乙醇通过促进对乙醇的厌恶反应来摄入。最近，我们观察到由LC引起的NE电路和直接支配腹侧盖区域（VTA）的A2，这对于调节两个奖励至关重要和厌恶。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量或乙醇的厌恶特性。提出的实验从逻辑上流出原始赠款，但会大大提高我们对1的新型机制的理解）揭示了调节暴饮暴食的乙醇摄入量和乙醇的厌恶特性的新型NE+电路，2）识别涉及的肾上腺肾上腺素受体（AR），3）识别AR的神经塑性变化重复的循环产生的RMTG，PBN和VTA中神经元特异性群体的表达像乙醇的摄入量。随着所调查的机制和NE电路的关注很少对神经生物学对乙醇的反应，拟议的研究是高度新颖和创新的。