Modulation of Effects of Repeated Ethanol Administratio*

描述（由申请人提供）： 我们的目标是确定在神经化学发生的变化， 长期饮酒后杏仁核延长，并检查 假设内源性K-阿片受体（KOR）系统减弱了 酒精的神经化学和行为影响。我们假设激活 KOR系统的酒精是一个关键的自我平衡机制，反对 酒精依赖的发展，以及KOR系统的失调 导致对酒精强化作用的脆弱性改变， 酒精成瘾我们将在1999年检验这些假设。 野生型小鼠，以及通过使用基因组成性缺失的小鼠 编码KOR-1受体或强啡肽，内源性KOR配体。具体 目标1将描述多巴胺，GABA和谷氨酸的变化 神经传递发生在丘脑核（Acb）和中央 慢性酒精戒断时杏仁核的变化 并确定KOR系统的功能减退是否加剧了这些效应。 采用定量微透析的无净通量法进行监测 细胞外多巴胺浓度和多巴胺摄取的变化， release.常规透析将用于测量基础和刺激 （酒精，KCI）诱发的多巴胺、GABA和谷氨酸流出。具体目标2 将决定KOR系统的功能减退是否会改变 长期饮酒后出现的行为。我们将测量 酒精戒断和戒断致敏的躯体体征 酒精中毒反复发作后出现的反应， 戒断具体目标3将确定KOR系统是否功能减退 导致对乙醇的奖励作用的敏感性增加， 多巴胺动力学是否在小鼠的Acb和杏仁核中改变 自我控制酒精操作性口服酒精自我管理将是 用于表征酒精和微透析的奖励作用， 用于监测自我给药小鼠的神经递质动力学。的 从这些研究中获得的数据将描述发生在 依赖性和非依赖性酒精后的杏仁核延长 给药和内源性阿片样物质系统在调节 酒精、酒精依赖和奖赏的神经化学作用。

DESCRIPTION (provided by applicant): Our goals are to identify alterations in neurochemistry that occur in the extended amygdala following chronic alcohol administration and examine the hypothesis that endogenous K-opioid receptor (KOR) systems attenuate the neurochemical and behavioral effects of alcohol. We postulate that activation of KOR systems by alcohol is a key homeostatic mechanism that opposes the development of alcohol dependence, and that dysregulation of KOR systems results in altered vulnerability to the reinforcing effects of alcohol and to alcohol addiction. We will test these postulates pharmacologically in wild-type mice, and by using mice with constitutive deletion of the gene encoding the KOR-1 receptor or dynorphin, the endogenous KOR ligand. Specific Aim 1 will characterize alterations in dopamine, GABA and glutamate neurotransmission that occur in the nucleus accumbens (Acb) and central nucleus of the amygdala during abstinence from chronic alcohol administration and determine whether hypofunction of KOR systems exacerbates these effects. The no net flux method of quantitative microdialysis will be used to monitor extracellular dopamine concentrations and changes in dopamine uptake and release. Conventional dialysis will be used to measure basal and stimulus (alcohol, KCI)- evoked dopamine, GABA and glutamate efflux. Specific Aim 2 will determine whether hypofunction of KOR systems alters adaptations in behavior that occur following chronic alcohol administration. We will measure somatic signs of alcohol withdrawal and sensitization of the withdrawal response that occurs after repeated bouts of alcohol intoxication and withdrawal. Specific Aim 3 will determine whether KOR system hypofunction results in increased sensitivity to the rewarding effects of ethanol and whether dopamine dynamics are altered in the Acb and amygdala of mice self-administering alcohol. Operant oral alcohol self- administration will be used to characterize the rewarding effects of alcohol and microdialysis will be used to monitor neurotransmitter dynamics in self-administering mice. The data derived from these studies will delineate neuroadaptations that occur in the extended amygdala following both context-dependent and independent alcohol administration and the role of endogenous opioid systems in modulating the neurochemical effects of alcohol, alcohol dependence, and reward.