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

描述(由申请人提供)： 背景：酒精的病理性使用是VHA面临的一大公共卫生挑战。在从伊拉克和阿富汗返回的士兵中，酒精中毒是最常见的初始精神障碍之一。有必要为酒精中毒和酒精中毒开发有效的治疗方法。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，可以阻断GABAA受体上乙醇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，苯二氮卓类反向激动剂，而不是苯二氮卓类拮抗剂，在多个水平上减弱了乙醇的影响。它们可减弱乙醇刺激的氯离子内流，从而影响乙醇的奖赏、镇静、共济失调和遗忘效应，乙醇的区别性刺激效应，乙醇激发的操作者行为和乙醇自身给药。然而，这还没有在人类身上表现出来。假设：GABAA苯二氮卓类部分反向激动剂Iomazenil将减轻健康受试者中乙醇中毒的几种措施。方法：采用随机、双盲、安慰剂对照、平衡、2×2交叉设计，健康受试者先静脉注射乙醇，然后静脉注射异马西尼。在服药前、服药期间和服药后多次收集中毒措施。汽车驾驶将使用驾驶模拟器进行评估。认知功能将使用视觉新奇怪异范式进行评估。在驾驶模拟器和新奇古怪任务期间记录脑电，以便分析与犯错相关的ERP成分(错误相关负波，ERN；驾驶模拟器)和目标(P3b)和新奇(P3a)检测(奇怪任务)。此外，神经的同步性 将在两个任务期间测量活动。小脑功能也将通过眨眼进行测试 条件反射。初步结果：Iomazenil和酒精可以安全使用(n=5)。Iomazenil可减轻酒精中毒和酒精诱导的驾驶损伤(n=5)。最后，当乙醇降低P300波幅时，异马西尼增加P300波幅。

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.