PHARMACOLOGIC TREATMENT OF ETHANOL WITHDRAWAL

乙醇戒断的药理学治疗

基本信息

批准号：
2045814
负责人：
HARBANS LAL
金额：
$ 22万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-30 至 1998-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2045814
关键词：
NMDA receptors adenosine alcoholism /alcohol abuse alcoholism /alcohol abuse chemotherapy benzodiazepines calcium channel blockers chordate locomotion cognition disease /disorder model drug withdrawal female inhibitor /antagonist laboratory rat nonhuman therapy evaluation serotonin stimulant /agonist

项目摘要

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.

这项研究的目的是识别和建立临床前选定药物预防和治疗急性和治疗的功效在乙醇依赖性动物模型中，长期戒断综合征。要研究的药物将从以下选择中选择药理学类：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男性和雌性大鼠。他们会成为通过在营养中施用乙醇来依赖乙醇液体饮食平衡或通过吸入进行给药。乙醇戒断将被衡量为符号（明显的行为）和症状（预测主观效应的行为）在停止时发生乙醇给药。感兴趣的药物将被施用与乙醇或撤离发生期间综合征。有效的药物预计将减轻无需戒断代替乙醇本身或引起乙醇的拮抗作用药理。这些动物将在他们的血液乙醇浓度降至可忽略的水平，而从急性阶段恢复后，它们长期戒断提取。在旷日持久的阶段，戒断的通常迹象已经完全消退，主要症状大大减轻。一个在此阶段将研究不同的症状。这些症状是基于人类的报告，但动物模型是稍后为他们开发。它们包括预测焦虑的行为，引人注目的脑状态，渴望酒精和许多缺陷在认知能力中。这些持久戒断的症状是重要，因为它们提供了食用酒精以避免的动力他们的发生，即使患者被阻止寻求酒精愉快。将选择少量药物表征其行为药理学以预测他们的安全。这项研究很重要，因为它回应了其中一项 RFA目标并承诺可能与酗酒和预防的治疗中连续酗酒人类主题。它还将提供有关药理治疗的数据女性受试者的酒精中毒。