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：病理性饮酒是 VHA 面临的一项重大公共卫生挑战。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。需要开发针对酒精中毒和酗酒的有效治疗方法。乙醇对突触外 GABAA 受体的刺激在很大程度上影响了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，苯二氮卓类反向激动剂（而非苯二氮卓类拮抗剂）在许多水平上减弱乙醇的作用。它们减弱乙醇刺激的Cl-流入，从而影响乙醇的奖励作用、镇静作用、共济失调作用和遗忘作用、乙醇的辨别刺激作用、乙醇激发的操作行为和乙醇自我管理。然而，这一点尚未在人类身上得到证实。假设：GABAA 苯二氮卓类部分反向激动剂 iomazenil 将减轻健康人类受试者的乙醇中毒的多种症状。方法：在随机、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，然后静脉注射碘马西尼。将在给药前、给药期间和给药后多次收集中毒测量结果。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颖的奇怪范式进行评估。在驾驶模拟器和新颖奇特任务期间将记录 EEG，以便分析与犯错相关的 ERP 组件（错误相关消极性，ERN；驾驶模拟器）以及目标 (P3b) 和新颖性 (P3a) 检测（奇怪任务）此外，神经元的同步性 将在这两项任务期间测量活动。小脑功能也将使用眨眼法进行测试 调理。初步结果：碘马西尼和酒精可以安全给药（n=5）。碘马西尼可减轻酒精中毒并减少酒精引起的驾驶障碍 (n=5)。最后，虽然乙醇降低了 P300 振幅，但碘马西尼却增加了它。