Dependence Driven Alterations in Ethanol Reinforcement

乙醇强化中的依赖性驱动的改变

基本信息

批准号：
7291098
负责人：
CHRISTOPHER L CUNNINGHAM
金额：
$ 27.91万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7291098
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 Condition Consumption Control Animal Control Groups Daily 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 Numbers Pattern Performance Personal Satisfaction Phase Phenotype Prevention strategy Procedures Process Protocols documentation Range Rattus Research Resources Rewards Schedule Self Administration Series Solutions Standards of Weights and Measures System Taste Perception Testing Tube Variant Water alcohol exposure alcohol reinforcement alcohol sensitivity binge drinking day design drinking experience improved indexing interest mouse model neuroadaptation preference research study size

项目摘要

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.

描述（由申请人提供）：该 INIA 联盟 U01 项目的重点是大脑回路中的遗传差异和神经适应，这些差异和大脑回路中的神经适应导致个体对过量饮酒的脆弱性存在差异。我们将使用胃内消耗（IGC）模型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）几天，然后进行自我输注测试程序，其中自愿摄入乙醇（或水）。调味溶液与 IG 乙醇搭配。此前，我们发现被动暴露乙醇会增强 IGC 和对乙醇配对风味（与水配对风味相比）的偏好，并且在大鼠和小鼠中随基因型的变化而变化。我们现在建议主要关注小鼠。目标 1 将检查两个近交系 C57BL/6J 和 DBA/2J 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）每日乙醇输注次数，以及（c）被动暴露乙醇的天数。目标 2 将通过扩展模型来表征 15 个标准近交菌株中的 IGC，进一步解决对依赖性驱动的乙醇强化敏感性的遗传差异的假设，从而允许检查 IGC 与先前研究的各种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，我们还将检查与全脑基因表达的遗传相关性。目标 3 将使用条件位置偏好程序和有限访问操作性自我管理来测试被动 IG 乙醇暴露是否会产生乙醇强化/奖励的变化。目标 4 将涉及与其他 INIA 项目的合作，通过测试两种小鼠模型，这些模型是针对酗酒过程中的高血液乙醇浓度而选择性培育的：（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在被动乙醇暴露后影响 IGC 增强的特定大脑区域。该项目的长期目标是了解导致人类酗酒的过量饮酒背后的遗传和神经生物学过程。通过提高对这些过程的理解，我们可以确定更有效的治疗和预防策略。