PHARMACOLOGIC TREATMENT OF ETHANOL WITHDRAWAL

这项研究的目标是确定和建立临床前 选择药物防治急性和慢性阻塞性肺疾病的疗效 酒精依赖动物模型中的稽延性戒断综合征。 被调查的药物将从下列药物中选择 药理类：苯二氮卓类混合激动剂/拮抗剂；5- 羟色胺激动剂和拮抗剂，腺苷拮抗剂， N-甲基-D-天冬氨酸拮抗剂和钙通道拮抗剂。测试 受试者将是成年雄性和雌性老鼠。它们将被制造出来 酒精依赖，通过在营养上给予乙醇 平衡流质饮食或吸入给药。乙醇 戒断将以体征(显性行为)和症状来衡量 (预测主观效果的行为)停止时发生的 乙醇管理部门。感兴趣的药物将被给予 与乙醇一起使用或在戒断过程中使用 综合症。有效的药物有望在没有戒断的情况下缓解戒断 替代乙醇本身或造成乙醇的拮抗 药理学。将对这些动物进行急性戒断的研究 他们的血液酒精浓度下降到可以忽略不计的水平， 在他们从急性期恢复后的长期戒断 戒烟。在旷日持久的阶段，通常的撤军迹象 已完全消退，主要症状大大减轻。一个 在此阶段将调查不同的症状集。这些 症状是基于人类的报告，但动物模型是 后来为他们开发的。它们包括预测焦虑的行为， 持续抽搐的大脑状态，对酒精的渴求，以及一些缺陷 在认知能力上。这些长期戒断的症状是 重要的是因为它们提供了饮酒的动力，以避免 即使在患者不愿饮酒的情况下也会发生这种情况 为了享乐。少数药物将被选为 他们的行为药理学特征，以预测他们的 安全。这项研究具有重要意义，因为它回应了 RFA的目标和承诺的临床前数据可能直接相关 青少年酒精中毒的治疗与持续酗酒的预防 人类受试者。它还将提供有关药物治疗的数据 女性受试者中酗酒的可能性。

The objective of this research is to identify and establish preclinical efficacy of selected drugs for prevention and treatment of acute and protracted withdrawal syndromes in animal models of ethanol dependence. The drugs to be investigated will be selected from the following pharmacological classes: benzodiazepine mixed agonist/ antagonists; 5- hydroxytryptamine agonists and antagonists, adenosine antagonists, N-methyl-D-aspartate antagonists, and calcium channel antagonists. Test subjects will be adult male and female rats. They will be made ethanol-dependent by administering ethanol either in a nutritionally balanced liquid diet or by administering it through inhalation. Ethanol withdrawal will be measured as signs (overt behaviors) and symptoms (behaviors predictive of subjective effects) occurring upon cessation of the ethanol administration. The drugs of interest will be administered either along with ethanol or during the occurrence of the withdrawal syndrome. Efficacious drugs are expected to alleviate withdrawal without substituting for ethanol itself or causing antagonism of ethanol's pharmacology. The animals will be studied for acute withdrawal after their blood ethanol concentrations decline to negligible levels, and for protracted withdrawal after they recover from the acute phase of withdrawal. During the protracted phase, the usual signs of withdrawal have subsided completely and the major symptoms are reduced greatly. A different set of symptoms will be investigated during this phase. These symptoms are based upon reports from humans but animal models were developed for them later. They include behaviors predictive of anxiety, proconvulsive brain state, craving for alcohol, and a number of deficits in cognitive abilities. These symptoms of protracted withdrawal are important because they provide motivation to consume alcohol to avoid their occurrence, even when patients are deterred from seeking alcohol for pleasure. A small number of drugs will be selected for characterization of their behavioral pharmacology to predict their safety. This research is significant because it responds to one of the RFA goals and promises preclinical data that may be directly relevant to the treatment of alcoholism and prevention continuous alcohol abuse in human subjects. It will also provide data on pharmacological treatment of alcoholism in female subjects.