BEHAVIORAL AND NEURAL CONCOMITANTS OF ETHANOL WITHDRAWAL

乙醇戒断的行为和神经并发症

• 批准号: 2667569
• 负责人: DARIN J KNAPP
• 金额: $ 8.93万
• 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/2667569
• 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.

从慢性酒精暴露中戒除可能伴随着强烈的 焦虑-戒断综合症的一个组成部分 神经化学机制和相关的神经解剖部位尚不清楚。 最近的数据表明，空气喷雾诱导的超声波测量 大鼠戒断时的USV发声可能是一个特别的 相关模型用于评估观察到的焦虑增加 戒烟。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以及 在高架加迷宫中的行为。在急性发作期间对药物进行评估 戒除慢性酒精暴露是基于他们的 对已证实的5-羟色胺能受体亚型的影响 调节焦虑。一种苯二氮卓和一种NMDA拮抗剂将作为 这一系列实验的阳性对照。特定目标II将 确定Fos样免疫反应(Fos-LI)和c-Fos的大脑部位 MR-NA受药物治疗的影响，这些药物可以阻断空气中的烟雾 超声波发声并在高位患者中产生抗焦虑效果 加上酒精戒断过程中的迷宫。这一努力将确定具体的 在酒精戒断过程中激活的大脑区域，将允许 系统地测试特定部位的药物的抗焦虑效果。 特定目标III将确定注射药物的特定效果 超声发声、迷宫行为和Fos-Li的脑区 和c-fos基因在乙醇戒断时的表达。这最后一个目标将确定 Fos-LI和c-FOS mRNA表达区域可能与抗-FOS相关 这些药物的焦虑作用。这项工作将提供数据，将 量化5-羟色胺能系统调节症状的能力 戒断焦虑症，并将提示大脑区域和细胞 酒精戒断焦虑的机制。这些努力将 为更好地理解脑脊髓炎的神经解剖学基础 并为改善酒精戒断焦虑提供了一个框架 未来治疗这一症状的药物治疗策略。