Modulation of Effects of Repeated Ethanol Administratio*

描述(由申请人提供)： 我们的目标是确定发生在神经化学上的变化 慢性饮酒后杏仁核扩大，并检查 假设内源性K-阿片受体(KOR)系统减弱 酒精对神经化学和行为的影响。我们假设激活 酒精对KOR系统的影响是一个关键的动态平衡机制，它反对 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易感性改变，并 酗酒。我们将对这些假设进行药理学测试 野生型小鼠，并使用具有结构性基因缺失的小鼠 编码KOR-1受体或强啡肽，内源性KOR配体。特定的 目标1将描述多巴胺、GABA和谷氨酸的变化 伏核(ACB)和中枢神经系统的神经传递 慢性酒精戒断过程中杏仁核的变化 并确定KOR系统的功能缺陷是否加剧了这些影响。 将采用定量微渗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和 放手。传统的透析将被用来测量基础和刺激 (酒精，KCI)-诱发多巴胺、GABA和谷氨酸外流。具体目标2 将确定KOR系统的功能障碍是否会改变 长期饮酒后发生的行为。我们将衡量 酒精戒断的躯体体征及戒断的敏感化 反复饮酒后出现的反应和 戒烟。具体目标3将确定KOR系统是否失灵 结果增加了对乙醇奖励效应的敏感度 小鼠前叶和杏仁核中的多巴胺动力学是否发生改变 自我注射酒精。手术用口服酒精自我给药将是 用来描述酒精和微透析的奖赏效应 用于监测自我给药小鼠的神经递质动态。这个 从这些研究中获得的数据将描绘出发生在 上下文依赖和非依赖酒精对杏仁核的延伸作用 给药与内源性阿片系统在调节细胞周期中的作用 酒精、酒精依赖和奖赏的神经化学效应。

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.