Dependence Driven Alterations in Ethanol Reinforcement

描述(由申请人提供)：INIA Consortium U01项目的重点是大脑回路中的遗传差异和神经适应，这是导致个体对过度饮酒易感性差异的原因。我们将使用胃内消耗(IGC)模型来扩展我们之前的发现，在该模型中，通过慢性胃内(IG)插管被动暴露于乙醇(或水)数天后，进行自我输注测试程序，在该程序中，自愿摄入风味溶液与IG乙醇配对。此前，我们发现被动酒精暴露会增强大鼠和小鼠对乙醇配对口味(与水配对口味相比)的IGC和偏好，并随着基因的不同而不同。我们现在建议主要关注老鼠。目的1检测两个近交系C57BL/6J和DBA/2J被动输液阶段的关键参数。这些参数包括：(A)每次输液剂量和每日总剂量，(B)每日注射乙醇的次数，以及(C)被动酒精暴露的天数。目的2将通过扩展模型来描述15个标准近交系IGC的特征，从而进一步解决对依赖驱动的乙醇强化的敏感性的遗传差异的假设，允许检查IGC与先前研究的广泛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，我们还将检查与整个大脑基因表达的遗传相关性。目的3利用条件性位置偏爱程序和受限通路操作者自我给药，测试被动免疫球蛋白乙醇暴露是否在乙醇强化/奖赏方面产生变化。AIM 4将与INIA的其他项目合作，测试两种为在狂饮过程中血液中乙醇浓度较高而选择性培育的小鼠模型：(A)SHIG和SLAC系，以及(B)HDID系及其遗传控制(HS/NPT)。最后，在INIA神经回路图谱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酒精暴露后IGC增强的特定脑区。该项目的长期目标是了解导致人类酒精中毒的过度饮酒背后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.