Dependence Induced Changes in Ethanol Reinforcement

描述(由申请者提供)：该项目使用一种创新的胃内酒精消费(IGAC)动物(小鼠)模型，研究遗传背景和既往酒精经验对自愿饮酒的影响。最近对这一模型的研究表明，间歇性被动接触酒精(但不是水)会导致几种基因型鼠随后的酒精摄入量大幅增加，其中包括通常在饮酒过程中避免饮酒的基因型。我们的目的是检验一个普遍的假设，即个体对过量酒精摄取的易感性的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(即耐受性、依赖性、戒断和学习)具有重要作用。目的1研究近交系小鼠C57BL/6J(B6)和DBA/2J(D2)被动酒精暴露后自愿摄入量增加的可能药理学和行为学机制。研究将考察依赖增强酒精摄入量的特异性和持久性、压力水平、性情耐受性、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)，以及当小鼠在戒断急性阶段自我注入酒精时，酒精对配对味道的偏爱的能力。目的2将通过检验共同基因影响饮酒、IGAC和戒断严重程度的假说，为因饮酒偏好(HAP3/LAP3)或酒精戒断严重程度(WSP/WSR)不同而选择性培育的小鼠品系中依赖增加酒精摄入量的遗传机制提供新的信息。目的3将通过干扰三个被认为在依赖诱导的自愿酒精摄入量增加中发挥重要作用的候选大脑区域(杏仁核、尾侧黑质、伏隔核)，来确定介导酒精依赖依赖D2小鼠酒精摄入量增加的大脑系统。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，以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系统所起的作用。AIM 3还将提供有关在急性戒断的第一天因戒断缓解而产生的负面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.