Dependence Driven Alterations in Ethanol Reinforcement

描述（由申请人提供）：该INIA联盟U 01项目的重点是大脑回路中的遗传差异和神经适应性，这些差异和神经适应性是导致过度饮酒的个体差异的原因。我们将使用胃内消耗（IGC）模型扩展我们先前的研究结果，在该模型中，通过慢性胃内（IG）插管被动暴露于乙醇（或水）数天，然后进行自我输注测试程序，其中自愿摄入调味溶液与IG乙醇配对。以前，我们发现IGC和偏好的乙醇配对的味道（相比，水配对的味道）是增强被动乙醇暴露和不同的基因型在大鼠和小鼠的功能。我们现在建议主要关注小鼠。目的1将检查两个近交系C57 BL/6 J和DBA/2 J中被动输注阶段的关键参数。这些参数包括：（a）每次输注的剂量和每日总剂量，（B）每日乙醇输注的次数，和（c）被动乙醇暴露的天数。目的2将进一步解决依赖性驱动的乙醇强化的敏感性遗传差异的假设，通过扩展模型来表征15个标准近交系中的IGC，允许检查IGC和广泛的先前研究的乙醇表型之间的遗传相关性。在INIA科罗拉多基因阵列核心的支持下，我们还将研究与全脑基因表达的遗传相关性。目标3将测试是否被动IG乙醇暴露产生乙醇强化/奖励的变化，使用条件性位置偏好程序和有限的访问操作性自我管理。目标4将涉及与INIA其他项目的合作，通过测试两种小鼠模型，这些小鼠模型是针对酗酒程序中的高血液乙醇浓度而选择性繁殖的：（a）SHAG和SLAC系，以及（B）HDID系及其遗传控制（HS/Npt）。最后，在INIA神经回路映射和基因分型核心的支持下，Aim 5将使用c-Fos免疫组织化学和病变来识别影响被动乙醇暴露后IGC增强的特定脑区。该项目的长期目标是了解导致人类酗酒的过度饮酒的遗传和神经生物学过程。通过提高我们对这些过程的理解，我们可以确定更有效的治疗和预防策略。

DESCRIPTION (provided by applicant): This INIA Consortium U01 Project is focused on genetic differences and neuroadaptations in brain circuitry that are responsible for individual differences in vulnerability to excessive consumption of alcohol. We will extend our previous findings using an intragastric consumption (IGC) model in which several days of passive exposure to ethanol (or water) via a chronic intragastric (IG) cannula are followed by a self-infusion test procedure in which voluntary ingestion of a flavored solution is paired with IG ethanol. Previously, we found that IGC and preference for the ethanol-paired flavor (compared to a water-paired flavor) is enhanced by passive ethanol exposure and varies as a function of genotype in both rats and mice. We now propose to focus primarily on mice. Aim 1 will examine key parameters of the passive infusion phase in two inbred strains, C57BL/6J and DBA/2J. These parameters include: (a) dose per infusion and total daily dose, (b) number of daily ethanol infusions, and (c) number of days of passive ethanol exposure. Aim 2 will further address the hypothesis of genetic differences in sensitivity to dependence-driven ethanol reinforcement by extending the model to characterize IGC in 15 standard inbred strains, allowing examination of genetic correlations between IGC and a wide range of previously studied ethanol phenotypes. With support from the INIA Colorado Gene Array Core, we will also examine genetic correlations with whole brain gene expression. Aim 3 will test whether passive IG ethanol exposure produces changes in ethanol reinforcement/reward using the conditioned place preference procedure and limited access operant self-administration. Aim 4 will involve collaboration with other INIA projects by testing two mouse models that have been selectively bred for high blood ethanol concentrations in binge drinking procedures: (a) the SHAG and SLAC lines, and (b) the HDID line and its genetic control (HS/Npt). Finally, with support from the INIA Neurocircuitry Mapping and Genotyping Core, Aim 5 will use c-Fos immunohistochemistry and lesions to identify specific brain areas that influence the enhancement in IGC after passive ethanol exposure. The long-term goal of this project is to understand the genetic and neurobiological processes underlying the excessive drinking that contributes to alcoholism in humans. By improving our understanding of these processes, we can identify more effective treatment and prevention strategies.