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

点击翻译按钮获取中文摘要

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.