Dependence Induced Changes in Ethanol Reinforcement

依赖性引起的乙醇强化变化

• 批准号: 8369314
• 负责人: CHRISTOPHER L CUNNINGHAM
• 金额: $ 31.39万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369314
• 关键词: Abstinence; Acute; Address; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Area; Behavioral; Behavioral Mechanisms; Brain; Breeding; CXCR4 gene; Cues; Dependence; Development; Ethanol; Flavoring; Future; Genes; Genetic; Genotype; Goals; Heavy Drinking; Human; Inbred Strains Mice; Inbreeding; Individual Differences; Intake; Intervention; Learning; Mediating; Modeling; Mus; Negative Reinforcements; Neurobiology; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Phase; Physiological; Play; Prevention strategy; Procedures; Process; Relapse; Research; Resistance; Role; Seizures; Severities; Specificity; Stress; Substantia nigra structure; System; Taste Perception; Testing; Time; Training; Water; Withdrawal; alcohol effect; alcohol exposure; alcohol reinforcement; base; design; drinking; drinking behavior; effective therapy; experience; follow-up; improved; innovation; mouse model; natural hypothermia; neural circuit; neuroadaptation; neurobiological mechanism; pre-clinical research; preference; prevent; problem drinker; receptor; treatment strategy

DESCRIPTION (provided by applicant): This project examines the effects of genetic background and past experience with alcohol on voluntary alcohol intake using an innovative animal (mouse) model of Intragastric Alcohol Consumption (IGAC). Recent research with this model has shown that intermittent passive exposure to alcohol (but not water) produces a large increase in subsequent alcohol intake in several mouse genotypes, including genotypes that normally avoid alcohol in drinking procedures. Our aims are designed to test the general hypothesis that individual differences in vulnerability to excessive alcohol intake are jointly determined by environmental and genetic influences on alcohol-induced neuroadaptations that contribute importantly to the development of alcoholism in humans (i.e., tolerance, dependence, withdrawal and learning). Aim 1 will assess possible pharmacological and behavioral mechanisms of enhanced voluntary intake after passive ethanol exposure in two well-studied inbred mouse strains, the C57BL/6J (B6) and DBA/2J (D2). Studies will examine the specificity and persistence of dependence-enhanced alcohol intake, stress levels, dispositional tolerance, the decay of functional tolerance (to both alcohol hypothermia and alcohol-induced conditioned taste aversion) as well as alcohol's ability to condition preference to a paired flavor when mice self-infuse alcohol during the acute phase of withdrawal. Aim 2 will provide new information on genetic mechanisms involved in dependence-enhanced alcohol intake in mouse lines selectively bred for differences in alcohol drinking preference (HAP3/LAP3) or alcohol withdrawal severity (WSP/WSR) by testing the hypothesis that common genes influence alcohol drinking, IGAC and withdrawal severity. Aim 3 will identify brain systems that mediate dependence-enhanced alcohol intake in alcohol-dependent D2 mice by disrupting three candidate brain areas thought to play important roles in dependence-induced increases in voluntary alcohol intake (amygdala, caudolateral substantia nigra, nucleus accumbens). Initial studies will use temporary inactivation of these candidate areas during acute withdrawal to identify target areas for follow-up studies that will assess the roles played by specific neuropharmacological systems using receptor-specific drug pretreatments during acute withdrawal. Aim 3 will also provide new information on the time course of negative reinforcement produced by withdrawal relief during the first day of acute withdrawal. The long-term goal of this project is to understand the environmental, 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. PUBLIC HEALTH RELEVANCE: Our long-term goal is to understand the environmental, genetic and brain mechanisms that underlie excessive alcohol intake in human alcoholics. This project uses an innovative animal model to study basic processes related to alcohol reinforcement (positive and negative), tolerance, dependence and withdrawal, all of which are thought to affect the development of alcoholism as well as relapse after abstinence. Information obtained from this research could be especially useful in the future identification of pharmacological and other interventions to reduce alcoholic drinking behavior.

描述（由申请人提供）：该项目使用创新的胃内酒精消耗（IGAC）动物（小鼠）模型，研究遗传背景和过去的饮酒经验对自愿饮酒的影响。最近对该模型的研究表明，间歇性被动接触酒精（但不是水）会导致几种小鼠基因型（包括通常在饮酒过程中避免饮酒的基因型）随后的酒精摄入量大幅增加。我们的目的旨在检验这样一个普遍假设：过量饮酒的个体差异是由环境和遗传对酒精引起的神经适应的影响共同决定的，这些神经适应对人类酗酒的发展（即耐受性、依赖性、戒断性和戒断性）有重要贡献。学习）。目标 1 将评估两种经过充分研究的近交小鼠品系 C57BL/6J (B6) 和 DBA/2J (D2) 被动暴露于乙醇后增强自愿摄入的可能药理学和行为机制。研究将检查依赖性增强的酒精摄入量、压力水平、性格耐受性、功能耐受性的衰退（对酒精体温过低和酒精引起的条件性味觉厌恶）的特异性和持久性，以及酒精调节对配对风味偏好的能力当小鼠在戒断急性期自行注射酒精时。目标 2 将通过测试共同基因影响酒精的假设，提供有关因饮酒偏好差异 (HAP3/LAP3) 或酒精戒断严重程度 (WSP/WSR) 选择性培育的小鼠品系中依赖增强酒精摄入的遗传机制的新信息饮酒、IGAC 和戒断严重程度。目标 3 将通过破坏三个候选大脑区域（杏仁核、尾外侧黑质、伏核）来确定介导酒精依赖性 D2 小鼠酒精摄入依赖性增强的大脑系统，这三个候选大脑区域被认为在依赖性诱导的自愿酒精摄入量增加中发挥重要作用。初步研究将利用急性戒断期间这些候选区域的暂时失活来确定后续研究的目标区域，后续研究将评估急性戒断期间使用受体特异性药物预处理的特定神经药理学系统所发挥的作用。目标 3 还将提供关于急性戒断第一天期间戒断缓解所产生的负强化的时间过程的新信息。该项目的长期目标是了解导致人类酗酒的过度饮酒背后的环境、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。 公共健康相关性：我们的长期目标是了解人类酗酒者过量饮酒的环境、遗传和大脑机制。该项目使用创新的动物模型来研究与酒精强化（正向和负向）、耐受、依赖和戒断相关的基本过程，所有这些都被认为会影响酗酒的发展以及戒酒后的复发。从这项研究中获得的信息对于未来确定减少饮酒行为的药理学和其他干预措施特别有用。