Dependence Induced Changes in Ethanol Reinforcement

描述（由申请人提供）：本项目通过一种创新的动物（小鼠）胃内酒精消耗（IGAC）模型，研究遗传背景和过去饮酒经历对自愿饮酒的影响。该模型的最新研究表明，在几种基因型小鼠中，间歇性被动暴露于酒精（而不是水）会导致随后酒精摄入量的大幅增加，包括在饮酒过程中通常避免饮酒的基因型。我们的目的是测试一个一般假设，即个体对过量饮酒的脆弱性差异是由环境和基因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（即耐受性、依赖性、戒断和学习）有重要影响。目的1将评估两种已被充分研究的近交系小鼠C57BL/6J （B6）和DBA/2J （D2）被动接触乙醇后自愿摄入增加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（对酒精低温和酒精诱导的条件性味觉厌恶），以及当小鼠在急性戒断期自我注入酒精时，酒精对配对味道的偏好能力。Aim 2将通过测试常见基因影响饮酒、IGAC和戒断严重程度的假设，为选择性繁殖的小鼠品系中酒精摄入依赖性增强的遗传机制提供新信息，这些小鼠品系的酒精偏好（HAP3/LAP3）或酒精戒断严重程度（WSP/WSR）存在差异。目的3将通过破坏被认为在酒精依赖性诱导的自愿酒精摄入量增加中起重要作用的三个候选脑区（杏仁核、尾侧黑质、伏隔核），确定介导酒精依赖性增强的D2小鼠酒精摄入的脑系统。初步研究将在急性戒断期间使用这些候选区域的暂时失活来确定后续研究的目标区域，这些研究将在急性戒断期间使用受体特异性药物预处理来评估特定神经药理学系统所起的作用。目的3还将提供关于急性戒断第一天戒断缓解产生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 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.