Dependence Driven Alterations in Ethanol Reinforcement

描述（由申请人提供）：这个INIA联盟U01项目的重点是遗传差异和大脑回路中的神经适应，这些遗传差异和神经适应是导致过度饮酒易感性个体差异的原因。我们将使用灌胃消耗（IGC）模型扩展我们之前的研究结果，在该模型中，通过慢性灌胃（IG）插管被动暴露于乙醇（或水）数天后，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。先前，我们发现IGC和对乙醇配对风味（与水配对风味相比）的偏好通过被动乙醇暴露而增强，并且在大鼠和小鼠中随基因型的功能而变化。我们现在建议主要关注老鼠。目的1将检测两种自交系菌株C57BL/6J和DBA/2J被动输注期的关键参数。这些参数包括：(a)每次输注剂量和每日总剂量，(b)每日乙醇输注次数，(c)被动乙醇暴露天数。目的2将进一步解决遗传差异的假设，通过扩展模型，以表征15个标准自交品系的IGC，允许检查IGC与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。目的3将测试被动IG乙醇暴露是否使用条件位置偏好程序和有限通道操作性自我管理来产生乙醇强化/奖励的变化。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，这两种小鼠模型是在酗酒过程中选择性培育的高血液乙醇浓度：(a) SHAG和SLAC系，以及(b) HDID系及其遗传控制（HS/Npt）。最后，在INIA神经回路定位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确定被动乙醇暴露后影响IGC增强的特定脑区域。该项目的长期目标是了解过量饮酒导致人类酒精中毒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.