BEHAVIORAL AND NEURAL CONCOMITANTS OF ETHANOL WITHDRAWAL

乙醇戒断的行为和神经并发症

• 批准号: 2882024
• 负责人: DARIN J KNAPP
• 金额: $ 8.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882024
• 关键词: NMDA receptors; anxiety; benzodiazepines; drug screening /evaluation; drug withdrawal; ethanol; excitatory aminoacid; gas chromatography; inhibitor /antagonist; laboratory rat; messenger RNA; neuroanatomy; neuropharmacology; serotonin receptor; stressor; tranquilizer; vocalization

Withdrawal from chronic ethanol exposure can be accompanied by an intense anxiety---a component of the withdrawal syndrome for which the neurochemical mechanisms and relevant neuroanatomical sites are unknown. Recent data suggests that measurement of air puff-induced ultrasonic vocalizations USVs in rats during withdrawal may be a particularly relevant model for evaluating the increased anxiety observed during withdrawal. Based upon this model, Specific Aim I of the present proposal will evaluate the pharmacology of this behavioral response as well as behavior in the elevated plus maze. Drugs to be evaluated during acute withdrawal from chronic ethanol exposure are chosen based on their effects on serotonergic receptor subtypes that have been demonstrated to modulate anxiety. A benzodiazepine and an NMDA antagonist will serve as positive controls for this experimental series. Specific Aim II will identify brain sites where Fos-Like Immunoreactivity (Fos-LI) and c-Fos mRNA are affected by drug treatments that block air puff induced ultrasonic vocalizations and produce anxiolytic effects in the elevated plus maze during ethanol withdrawal. This effort will identify specific regions of brain activated during ethanol withdrawal and will allow for systematic testing of specific sites for anti-anxiety effects of drugs. Specific Aim III will determine the effects of drugs injected in specific brain regions on ultrasonic vocalizations, plus maze behavior, and Fos-LI and c-fos mRNA in ethanol withdrawal. This last aim will confirm which regions expressing Fos-LI and c-fos mRNA may be relevant to the anti- anxiety action of these drugs. This work will provide data that will quantify the capacity of the serotonergic system to modulate the symptom of withdrawal anxiety and will suggest brain regions and cellular mechanisms responsible for ethanol withdrawal anxiety. Such efforts will provide a better basis for understanding the neuroanatomical basis of ethanol withdrawal anxiety as well as provide a framework for improved pharmacotherapeutic strategies to treat this symptom in the future.

从慢性乙醇暴露中退出可能伴随着强烈的 焦虑-戒断综合征的一个组成部分， 神经化学机制和相关的神经解剖部位是未知的。 最近的数据表明，测量空气膨化引起的超声波 大鼠在戒断过程中的发声USV可能是一个特别的 相关模型，用于评估在治疗期间观察到的焦虑增加 戒断根据这一模式，本提案的具体目标一 将评估这种行为反应的药理学， 高架十字迷宫中的行为急性期评价药物 从慢性乙醇暴露中退出的选择是基于他们的 对肾上腺素能受体亚型的影响，已被证明， 调节焦虑苯二氮卓类和NMDA拮抗剂将作为 本实验系列的阳性对照。具体目标II将 确定Fos样免疫反应性（Fos-LI）和c-Fos mRNA受阻断空气抽吸诱导的药物治疗的影响， 超声发声，并产生抗焦虑作用，在升高的 加上乙醇戒断期间的迷宫。这项工作将确定具体的 大脑区域在酒精戒断期间被激活， 系统测试特定部位的药物抗焦虑作用。 具体目标III将确定药物注射在特定的 超声波发声，加上迷宫行为和Fos-LI的脑区 c-fos mRNA的表达。这最后一个目标将证实， Fos-LI和c-fos mRNA的表达区域可能与抗Fos-LI和c-fos mRNA的表达有关。 这些药物的作用。这项工作将提供数据， 量化肾上腺素能系统调节症状的能力 会提示大脑区域和细胞 酒精戒断焦虑的机制 这种努力将 为理解神经解剖学基础提供了更好的基础， 乙醇戒断焦虑，以及提供一个框架，改善 药物治疗策略，以治疗这种症状的未来。