Dependence Driven Alterations in Ethanol Reinforcement

这个INIA联盟U 01项目的重点是遗传差异和大脑回路的神经适应性 这是造成个体对过量饮酒的脆弱性差异的原因。我们将 使用胃内消耗（IGC）模型扩展了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），然后进行自我输注 自愿摄入调味溶液与IG乙醇配对的测试程序。此前我们 发现IGC和对乙醇配对风味的偏好（与水配对风味相比）增强 在大鼠和小鼠中，通过被动乙醇暴露，并作为基因型的函数而变化。我们现建议 主要集中在老鼠身上。目的1将检查两个近交系动物被动输注阶段的关键参数 菌株C57 BL/6 J和DBA/2 J。这些参数包括：（a）每次输注的剂量和每日总剂量，（B） 每日乙醇输注次数，和（c）被动乙醇暴露天数。目标2将进一步 解决依赖性驱动的乙醇强化敏感性的遗传差异的假设， 扩展模型，以表征15个标准近交系中的IGC，允许检查遗传 IGC和以前研究的乙醇表型之间的相关性。的支持下 INIA科罗拉多基因阵列核心，我们还将研究与全脑基因的遗传相关性 表情目标3将测试被动IG乙醇暴露是否会导致乙醇 强化/奖励使用条件位置偏好程序和限制访问操作 自我管理。Aim 4将通过测试两个小鼠模型与其他INIA项目合作 已经被选择性地培育用于在狂饮程序中的高血液乙醇浓度：（a） SHAG和SLAC系，和（B）HDID系及其遗传对照（HS/Npt）。最后，在来自 INIA神经回路定位和基因分型核心，Aim 5将使用c-Fos免疫组织化学， 损伤，以确定影响被动乙醇后IGC增强的特定脑区 exposure.该项目的长期目标是了解遗传和神经生物学过程 导致人类酗酒的潜在原因。通过提高我们对 在这些过程中，我们可以确定更有效的治疗和预防战略。

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.