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，与个人和社会层面的重大成本和伤害风险相关。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酗酒，因此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的神经和遗传基础。神经肽Y（NPY）是一种与人类和动物模型中的酒精消耗有关的系统。因此，该项目的总体目标是确定神经肽Y在饮酒致醉的遗传模型中的作用。在黑暗中大量饮酒（HDID-1）小鼠被选择性地饲养，以在有限的饮酒后获得高血液酒精浓度，因此代表了酗酒样酒精消费风险的遗传模型。目的1将使用免疫组织化学来测量与酒精消耗相关的大脑区域中的NPY，这些大脑区域在遗传上具有酗酒的“风险”（HDID-1）和没有这种遗传易感性的小鼠（异质性股票; HS），以确定这些基因型是否在NPY水平上存在差异。然后，目标2将敲低杏仁核中央核中的Npy基因，其中HDID-1小鼠显示出比HS小鼠更高的Npy mRNA水平，以尝试以位点特异性的方式减少这些动物中的暴饮暴食。目标3将开始确定NPY系统的特定方面，该系统可以被调节以改变HDID-1小鼠的饮酒。NPY和NPY Y1受体（Y1 R）表达将在未接触乙醇和饮酒后的HS和HDID-1小鼠的CeA中定位。此外，将使用Y1 R拮抗剂向CeA中的位点特异性输注来尝试减少HDID-1小鼠的饮酒，这将有助于进一步剖析NPY在狂饮中的位点特异性作用。该提案将测试以下假设：在具有酗酒遗传风险的小鼠中，高Npy基因和蛋白质表达在一定程度上导致HDID-1系的高饮酒表型，并且CeA中的Y1 R是这种效应所必需的。

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.