Dependence Induced Changes in Ethanol Reinforcement

描述（由申请人提供）：本项目采用创新的动物（小鼠）胃内酒精消耗（IGAC）模型，研究遗传背景和过去的酒精经验对自愿酒精摄入量的影响。最近对这种模型的研究表明，间歇性被动暴露于酒精（而不是水）会导致几种小鼠基因型随后的酒精摄入量大幅增加，包括通常在饮酒过程中避免酒精的基因型。我们的目的是检验一个普遍的假设，即对过量酒精摄入的易感性的个体差异是由环境和遗传对酒精诱导的神经适应的影响共同决定的，这些神经适应对人类酒精中毒的发展有重要作用（即，容忍、依赖、退缩和学习）。目的1将评估可能的药理学和行为机制，增强自愿摄入被动乙醇暴露后，在两个良好的研究近交系小鼠品系，C57 BL/6 J（B6）和DBA/2 J（D2）。研究将检查依赖性增强的酒精摄入的特异性和持久性，压力水平，性格耐受性，功能耐受性的衰退（酒精低温和酒精诱导的条件性味觉厌恶）以及酒精的能力，条件偏好配对的味道时，小鼠在急性期的撤退自我注入酒精。目的2将提供新的信息，在依赖性增强酒精摄入的小鼠品系选择性繁殖的差异，饮酒偏好（HAP 3/LAP 3）或酒精戒断严重程度（WSP/WSR）通过测试的假设，共同的基因影响饮酒，IGAC和戒断严重程度的遗传机制。目的3将确定大脑系统，介导依赖性增强酒精摄入酒精依赖的D2小鼠，通过破坏三个候选脑区，被认为在依赖性诱导的自愿酒精摄入量增加（杏仁核，尾外侧黑质，丘脑核）中发挥重要作用。初步研究将在急性戒断期间暂时灭活这些候选区域，以确定后续研究的目标区域，这些研究将评估在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戒断缓解产生的负强化的时间进程的新信息。该项目的长期目标是了解导致人类酗酒的过度饮酒的环境，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。 公共卫生相关性：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（积极和消极），耐受性，依赖性和戒断有关的基本过程，所有这些都被认为会影响酒精中毒的发展以及戒酒后的复发。从这项研究中获得的信息可能在未来确定减少饮酒行为的药理学和其他干预措施方面特别有用。

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.