Ability of Partial Inverse Agonist, Iomazenil, to Block Ethanol Effects in Humans

描述（由申请人提供）： 背景：病理性饮酒是VHA面临的一个主要公共卫生挑战。在从伊拉克和阿富汗返回的士兵中，酗酒是最常见的初始精神疾病之一。有必要开发有效的治疗酒精中毒和酒精中毒。乙醇对突触外GABAA受体的刺激在很大程度上有助于其在与人类中毒相关的剂量下的作用。因此，能够阻断乙醇对GABAA受体作用的药物可能在酒精中毒和酒精中毒的治疗中发挥独特的作用。临床前研究表明，苯二氮卓类反相激动剂，而不是苯二氮卓类拮抗剂，在许多水平上减弱乙醇的影响。它们减弱乙醇刺激的Cl-内流，从而影响乙醇的奖励、镇静、共济失调和遗忘效应，乙醇的辨别刺激效应，由乙醇和乙醇自我给药激发的操作行为。然而，这一点尚未在人类身上得到证实。假设：GABAA苯二氮部分反向激动剂，iomazenil，将减轻健康人类受试者的乙醇中毒的几种措施。研究方法：在一项随机、双盲、安慰剂对照、平衡、2 x 2交叉设计中，健康受试者将接受静脉注射乙醇，然后静脉注射碘马替尼。将在给药前、给药期间和给药后多次采集中毒指标。汽车驾驶将使用驾驶模拟器进行评估。将使用视觉新奇古怪范例评估认知功能。将在驾驶模拟器和新奇古怪任务期间记录EEG，允许分析与犯错误（错误相关负性，ERN;驾驶模拟器）和目标（P3 b）和新奇（P3 a）检测（古怪任务）相关的ERP成分。 在这两项任务期间将对活动进行衡量。小脑功能也将通过眨眼测试 条件反射初步结果：Iomazenil和酒精可以安全地给药（n=5）。Iomazenil减轻了酒精中毒，减少了酒精诱导的驾驶障碍（n=5）。最后，当乙醇降低P300振幅时，iomazenil增加它。

DESCRIPTION (provided by applicant): Background: The pathological use of alcohol is a major public health challenge facing VHA. Among soldiers returning from Iraq and Afghanistan, alcoholism is one of the most common initial psychiatric disorders. There is a need to develop effective treatments for alcohol intoxication and alcoholism. The stimulation of extrasynaptic GABAA receptors by ethanol contributes substantially to its effects at doses associated with human intoxication. Therefore, drugs that could block ethanol actions at GABAA receptors might play a unique role in the treatment of alcohol intoxication and alcoholism. Preclinical studies suggest that benzodiazepine inverse agonists, but not benzodiazepine antagonists, attenuate the effects of ethanol on many levels. They attenuate ethanol-stimulated Cl- influx thereby affecting the rewarding, sedating, ataxic, and amnestic effects of ethanol, the discriminative stimulus effects of ethanol, operant behavior motivated by ethanol and ethanol self- administration. However, this has not yet been shown in humans. Hypothesis: The GABAA benzodiazepine partial inverse agonist, iomazenil, will attenuate several measures of ethanol intoxication in healthy human subjects. Methods: In a randomized, double-blind, placebo-controlled, counterbalanced, 2 x 2, crossover design, healthy subjects will receive intravenous ethanol followed by intravenous iomazenil. Measures of intoxication will be collected before, and several times during and after drug administration. Automobile driving will be assessed using a driving simulator. Cognitive function will be assessed using the visual novelty oddball paradigm. EEG will be recorded during the driving simulator and novelty oddball tasks, allowing for the analysis of ERP components related to making errors (error-related negativity, ERN; driving simulator) and target (P3b) & novelty (P3a) detection (oddball task) Additionally, the synchronicity of neural activity will be measured during both tasks. Cerebellar function will also be tested using eyeblink conditioning. Preliminary results: Iomazenil and alcohol can be administered safely (n=5). Iomazenil attenuated alcohol intoxication and reduced alcohol-induced driving impairments (n=5). Finally, while ethanol decreases P300 amplitude, iomazenil increases it.