The role of neuropeptide Y in binge-like drinking in mice

描述（由申请人提供）：酗酒是一种酒精消费模式，在个人和社会层面上与巨大的成本和危害风险相关。虽然酗酒通常是酒精使用障碍的一个组成部分，但没有可诊断问题的人也会酗酒，因此它与社会和研究人员有很大的相关性。为了提供预防或治疗策略来对抗这种高风险行为，我们需要更好地了解酗酒背后的神经和遗传基础。在人类和动物模型中，神经肽Y （NPY）是一个与饮酒有关的系统。因此，本项目的首要目标是确定NPY在饮酒到中毒的遗传模型中在狂饮样饮酒中的作用。在夜间高饮酒（HDID-1）小鼠被选择性地培育为在有限的饮酒后血液酒精浓度高的小鼠，因此代表了暴饮暴食风险的遗传模型。Aim 1将使用免疫组织化学方法测量酒精幼稚小鼠(具有酗酒遗传“风险”的小鼠（HDID-1）和没有这种遗传易感性的小鼠（异种库存；HS）中与酒精消耗相关的大脑区域的NPY，以确定这些基因型在NPY水平上是否存在差异。然后，Aim 2将敲除杏仁核中央核的Npy基因，HDID-1小鼠的Npy mRNA水平高于HS小鼠，试图以特定位点的方式减少这些动物的暴饮暴食。Aim 3将开始确定NPY系统的具体方面，这些方面可以通过调节来改变HDID-1小鼠的饮酒。NPY和NPY Y1受体（Y1R）在HS和HDID-1小鼠的CeA中表达。此外，将特异位点的Y1R拮抗剂输注到CeA中，将试图减少HDID-1小鼠的饮酒，这将有助于进一步剖析NPY在酗酒中的特异位点作用。这一提议将验证一个假设，即在具有酗酒遗传风险的小鼠中，Npy基因和蛋白质的高表达在一定程度上导致了HDID-1系的高饮酒表型，而CeA中的Y1Rs对这种效应是必要的。

DESCRIPTION (provided by applicant): Binge drinking is a pattern of alcohol consumption that is associated with significant cost and risk of harm at the level of the individual and societ. While binge drinking is frequently a component of alcohol use disorders, people without a diagnosable problem also binge drink and it is consequently of a great deal of relevance to society and researchers. In order to provide preventative or therapeutic strategies to combat this high-risk behavior, we need to better understand the neural and genetic substrates that underlie binge drinking. Neuropeptide Y (NPY) is one system that has been implicated in alcohol consumption in both humans and animal models. Consequently, the overarching goal of this project is to determine the role of NPY in binge-like drinking in a genetic model of drinking to intoxication. High Drinking in the Dark (HDID-1) mice have been selectively bred for high blood alcohol concentrations following limited access drinking, and consequently represent a genetic model of risk for binge-like alcohol consumption. Aim 1 will use immunohistochemistry to measure NPY in brain areas relevant to alcohol consumption in alcohol-naive mice that are genetically "at risk" for binge drinking (HDID-1) and mice that do not have this genetic susceptibility (heterogeneous stock; HS) to determine whether these genotypes differ in NPY levels. Aim 2 will then knock down the Npy gene in the central nucleus of the amygdala, where the HDID-1 mice show greater Npy mRNA levels than the HS mice, to attempt in a site-specific manner to reduce binge-like drinking in these animals. Aim 3 will begin to pinpoint specific aspects of the NPY system that could be modulated to alter drinking in the HDID-1 mice. NPY and NPY Y1 receptor (Y1R) expression will be mapped in the CeA in ethanol-na¿ve and post-drinking HS and HDID-1 mice. Additionally, site-specific infusion of Y1R antagonists into the CeA will be used to attempt to reduce drinking in the HDID-1 mice, which will serve to further dissect the site-specific role of NPY in binge drinking. This proposal will test the hypothesis tha high Npy gene and protein expression in mice at genetic risk for binge drinking are in part responsible for the high-drinking phenotype of the HDID-1 line, and that Y1Rs in the CeA are necessary for this effect. PUBLIC HEALTH RELEVANCE: Binge drinking is a risky behavior with significant cost at both the level of the individual and society. The long- term goal of this study is to determine the role of neuropeptide Y in genetic risk for binge drinking and begin to determine possible substrates within this system for therapeutic targeting.