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

部分反向激动剂 Iomazenil 阻断乙醇对人体影响的能力

• 批准号: 8536592
• 负责人: DEEPAK Cyril D'SOUZA
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536592
• 关键词: Affect; Afghanistan; Agonist; Alcohol consumption; Alcoholic Intoxication; Alcoholism; Alcohols; Animals; Antidotes; Attenuated; Automobile Driving; Benzodiazepines; Binding; Blinking; Cerebellum; Code; Crossover Design; Detection; Dose; Double-Blind Method; EP300 gene; Electroencephalography; Electrophysiology (science); Ethanol; Feeling; GABA Receptor; Genes; Genetic Polymorphism; Human; Impairment; Intoxication; Intravenous; Iraq; Laboratories; Learning; Long-Term Effects; Measures; Mental disorders; Methods; Naloxone; Naltrexone; Neuraxis; Neurobiology; Opioid; P300 Event-Related Potentials; Pharmaceutical Preparations; Placebo Control; Play; Public Health; Randomized; Rewards; Role; Self Administration; Simulate; Soldier; Stimulus; Synapses; Testing; Time; Visual; alcohol effect; cognitive function; conditioning; effective therapy; gamma-Aminobutyric Acid; human subject; iomazenil; motivated behavior; novel; preclinical study; receptor; relating to nervous system

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.

描述（由申请人提供）： 背景：酒精的病理使用是VHA面临的主要公共卫生挑战。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病之一。有必要开发有效的酒精中毒和酒精中毒治疗方法。通过乙醇刺激外突触GABAA受体，其在与人类中毒相关的剂量下的作用显着贡献。因此，可以阻止GABAA受体乙醇作用的药物在治疗酒精中毒和酒精中毒的治疗中起着独特的作用。临床前研究表明，苯二氮卓类反向激动剂，但没有苯二氮卓类拮抗剂，可减弱乙醇在许多水平上的影响。它们减弱了乙醇刺激的cl胞体，从而影响乙醇的奖励，镇静，共济失调和柔和作用，乙醇的歧视性刺激作用，乙醇和乙醇自我给药的动作行为。但是，这尚未在人类中显示。假设：GABAA苯二氮卓类药物部分反激动剂Iomazenil将减轻健康人类受试者中乙醇中毒的几种措施。方法：在随机，双盲，安慰剂对照，平衡的情况下，2 x 2，跨界设计，健康受试者将接受静脉内乙醇，然后接受静脉内iomazenil。在药物给药期间和之后，将收集中毒的措施。将使用驾驶模拟器评估汽车驾驶。认知功能将使用视觉新颖性奇数范式进行评估。脑电图将在驾驶模拟器和新颖性奇数球任务期间记录，以分析与犯错（与错误相关的消极情绪，ERN；驾驶模拟器）和目标（P3B）和新颖性（P3A）和新颖（P3A）检测（ODDBALL任务）相关的ERP组件。 活动将在两个任务期间衡量。小脑功能也将使用Eykeblink进行测试 调理。初步结果：可以安全地管理iomazenil和酒精（n = 5）。 iomazenil减轻了酒精中毒，并减少了酒精诱导的驾驶障碍（n = 5）。最后，虽然乙醇降低了p300幅度，但iomazenil却增加了它。