Dependence Driven Alterations in Ethanol Reinforcement

乙醇强化中的依赖性驱动的改变

• 批准号: 7683804
• 负责人: CHRISTOPHER L CUNNINGHAM
• 金额: $ 29.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683804
• 关键词: Address; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Animal Model; Animals; Area; Behavioral; Blood; Boutos; Brain; Brain Mapping; Breeding; Cannulas; Chronic; Collaborations; Colorado; Consumption; Control Animal; Control Groups; Data; Databases; Dependence; Dissection; Dose; Ethanol; Exposure to; FOS gene; Flavoring; Gene Expression; Genes; Genetic; Genetic Variation; Genotype; Goals; Heavy Drinking; Histocytochemistry; Histology; Human; Immunohistochemistry; Inbred Strain; Inbred Strains Mice; Individual Differences; Infusion procedures; Ingestion; Intake; Intravenous; Knowledge; Laboratories; Lesion; Literature; Maps; Measures; Modeling; Molecular; Mus; Neurobiology; Pattern; Performance; Phase; Phenotype; Prevention strategy; Procedures; Process; Protocols documentation; Rattus; Research; Resources; Rewards; Schedule; Self Administration; Series; Solutions; System; Taste Perception; Testing; Tube; Variant; Water; alcohol exposure; alcohol reinforcement; alcohol sensitivity; binge drinking; design; drinking; effective therapy; experience; improved; indexing; interest; mouse model; neuroadaptation; preference; research study

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.

INIA 联盟 U01 项目专注于大脑回路中的遗传差异和神经适应 这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）模型扩展了我们之前的发现，其中几天 通过慢性胃内 (IG) 插管被动接触乙醇（或水），然后进行自我输注 自愿摄入调味溶液与 IG 乙醇搭配的测试程序。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 由被动乙醇暴露引起，并且在大鼠和小鼠中随基因型的变化而变化。我们现在提议 主要关注小鼠。目标 1 将检查两个近交系被动输注阶段的关键参数 菌株，C57BL/6J 和 DBA/2J。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，以及 (c) 被动接触乙醇的天数。目标2将进一步 通过以下方式解决了对依赖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 个标准近交系的 IGC，从而可以检查遗传 IGC 与先前研究的各种乙醇表型之间的相关性。在来自的支持下 INIA科罗拉多基因阵列核心，我们还将检查与全脑基因的遗传相关性 表达。目标 3 将测试被动 IG 乙醇暴露是否会产生乙醇变化 使用条件位置偏好程序和限制访问操作进行强化/奖励 自我管理。目标 4 将通过测试两种小鼠模型与其他 INIA 项目进行合作 已针对酗酒过程中的高血液乙醇浓度进行了选择性培育：(a) SHAG 和 SLAC 系，以及 (b) HDID 系及其遗传控制 (HS/Npt)。最后，在大家的支持下 INIA 神经回路图谱和基因分型核心，目标 5 将使用 c-Fos 免疫组织化学和 损伤以确定影响被动乙醇后 IGC 增强的特定大脑区域 接触。该项目的长期目标是了解遗传和神经生物学过程 过量饮酒导致人类酗酒。通过提高我们的理解 通过这些过程，我们可以确定更有效的治疗和预防策略。