PHARMACOTHERAPY FOR MULTIPLE ETHANOL WITHDRAWALS

长期饮酒的严重后果之一是 身体依赖和体验生活的可能性- 戒断综合征的威胁 各种药物制剂 用于乙醇（EtOH）戒断的医疗管理。 然而，尽管大量的努力集中在评估治疗上， 在一次戒断发作中，很少有人注意到 针对多次EtOH戒断经历对 治疗效果，以及治疗的选择。 这是特别 考虑到酗酒者的高再犯率，沿着 事实上，许多接受治疗的酒精中毒患者都有 之前无数次戒毒经历的证据 因此，本提案 专注于评价多次乙醇戒断的药物治疗。 我们最近建立了乙醇戒断的动物模型， 证明了既往EtOH戒断经验的增强作用。 这一点，沿着其他实验和临床证据提供支持 酒精戒断的点燃假说 虽然这项工作 重点关注的是， 戒断（癫痫发作），似乎有效的治疗还需要 针对EtOH线索的心理（焦虑）和主观感知） 戒断综合征的组成部分，鉴于潜在的重要性， 这些变量在恢复饮酒的动机中。 拟议工作 将使用已建立的多次乙醇提取模型来评价 各种药物治疗在治疗物理以及 心理和主观方面的戒断综合征。 虽然阐明机制不是临床的主要目标- 面向项目，相关基础研究成果提供了指导 以及选择待评价药物的理由。 更 具体而言，我们选择首先将调查重点放在毒品上， 激活GABA α，谷氨酸（NMDA和非NMDA），和电压操作 钙通道受体系统。 非镇静剂的作用 还将检查抗惊厥药。 这些药物已被选定 因为它们针对的神经化学系统（a）表现出神经适应性 可能导致EtOH戒断的慢性EtOH暴露变化 症状和（B）参与神经元可塑性事件（其可能是 类似于点燃过程）。 因此，这些药物可能特别适合 对于有以下病史的患者， 多次提取乙醇 总的来说，拟议的工作可以提供 重要的临床相关信息， 治疗急性乙醇戒断的药物治疗策略，以及 长期管理乙醇依赖和酒精中毒。

One of the serious consequences of chronic alcohol use is the development of physical dependence and the possibility of experiencing a life- threatening withdrawal syndrome. A variety of pharmacologic agents have been used for the medical management of ethanol (EtOH) withdrawal. However, while a great deal of effort has focused on evaluating treatment of a single withdrawal episode, very little attention has been directed toward the potential impact of multiple EtOH withdrawal experiences on treatment efficacy, as well as choice of treatment. This is particularly relevant given the high rate of recidivism among alcoholics, along with the fact that many alcoholic patients presenting for treatment have a history of numerous prior detoxification experiences. Accordingly, this proposal is focused on evaluating pharmacotherapy for multiple EtOH withdrawals. We have recently established an animal model of EtOH withdrawal that demonstrates the potentiating effects of prior EtOH withdrawal experiences. This, along with other experimental and clinical evidence provide support for the kindling hypothesis of alcohol withdrawal. While much of this work has focused on the progressive intensification of physical symptoms of withdrawal (seizures), it would seem that effective treatment needs to also target the psychological (anxiety) and subjective perception of EtOH cues) components of the withdrawal syndrome, given the potential importance of these variables in the motivation to resume drinking. The proposed work will use an established model of multiple EtOH withdrawals to evaluate the efficacy of various pharmacotherapies in treating physical as well as psychological and subjective aspects of the withdrawal syndrome. While elucidation of mechanisms is not the primary goal of this clinically- oriented project, relevant basic research findings have provided guidance and a rationale for the selection of drugs to be evaluated. More specifically, we have chosen to initially focus our investigation on drugs active at the GABAa, glutamate (NMDA and non-NMDA), and voltage-operated calcium channel receptor systems. The effects of non-sedative anticonvulsants will be examined as well. These drugs have been selected because they target neurochemical systems that (a) exhibit neuroadaptive changes to chronic EtOH exposure which may underlie EtOH withdrawal symptoms and (b) are involved in neuronal plasticity events (which may be akin to the kindling process). Thus, these drugs may be particularly appropriate with regard to treatment for patients with a history of multiple EtOH withdrawals. Taken together, the proposed work may provide important clinically-relevant information regarding more effective pharmacotherapy strategies for treating acute EtOH withdrawal, as well as long-term management of EtOH dependence and alcoholism.