The Effect of Brief Potent Glutamatergic Modulation on Disordered Alcohol Use

描述（由申请人提供）：谷氨酸神经传递的改变被认为是酒精依赖药物治疗的重要靶点。我们对氯胺酮（一种具有强效前额叶效应的谷氨酸调节剂）的初步研究表明，它独特地解决了与有问题的药物和酒精使用相关的神经适应问题。除了安全地给予活跃的吸毒者外，我们发现亚麻醉剂氯胺酮在输注后24小时与活性对照相比，显着增加了停止使用可卡因的动机，并降低了线索诱导的渴望。一项正在进行的临床试验也表明，氯胺酮可以在门诊成瘾治疗的环境中可行。在这些发现的基础上，该项目旨在研究氯胺酮是否会使临床环境中的问题酒精使用受益。我们将评估单次亚麻醉剂量的氯胺酮（0.11 mg/kg，2分钟内，随后0.60 mg/kg，50分钟内）对40名参与动机增强治疗（MET）的非抑郁酒精依赖者的酒精依赖的影响。我们预测，与活性对照咪达唑仑相比，氯胺酮将显著降低重度饮酒天数百分比。第二个目的是关于氯胺酮对酒精相关缺陷的影响，这些缺陷涉及前额功能障碍 或谷氨酸异常，如压力敏感性、渴望、退缩、冲动、低自我效能和低正念。因此，我们的目标是以能够对实地作出重要贡献的方式评价一项高度创新的干预措施。氯胺酮对这些结果的影响表明，短暂有效的多巴胺能调节是一种值得进一步研究的酒精依赖可能的治疗策略。

DESCRIPTION (provided by applicant): Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for alcohol dependence. Our preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest that it uniquely addresses neuroadaptations related to problematic drug and alcohol use. Alongside being safely administered to active drug users, we found that sub-anesthetic ketamine significantly increased motivation to stop cocaine use and decreased cue-induced craving when compared to an active control, 24 hours post-infusion. An ongoing clinical trial also indicates that ketamine can be feasibly administered in the setting of outpatient addiction treatment. Expanding on these findings, this project aims to examine whether ketamine will benefit problematic alcohol use in clinical settings. We will evaluate the effect of a single sub-anestheti dose of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on alcohol dependence in 40 non-depressed alcohol-dependent individuals engaged in Motivational Enhancement Therapy (MET). We predict that, compared to the active control midazolam, ketamine will significantly reduce percentage heavy drinking days. Secondary aims pertain to the effect of ketamine on alcohol-related deficits that implicate prefrontal dysfunction or glutamate abnormalities, such as stress sensitivity, craving, withdrawal, impulsivity, low self-efficacy, and low mindfulness. Thus, we aim to evaluate a highly innovative intervention in a manner that has the capacity to make important contributions to the field. An effect of ketamine on these outcomes would suggest that brief potent glutamatergic modulation represents a possible treatment strategy for alcohol dependence that merits further investigation.