The Effect of Brief Potent Glutamatergic Modulation on Disordered Alcohol Use

描述(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。我们对氯胺酮的初步研究表明，它是一种具有强大的前额叶效应的谷氨酸调节剂，它独特地解决了与有问题的药物和酒精使用有关的神经适应问题。除了安全地给活跃的吸毒者使用外，我们发现亚麻醉剂氯胺酮显著增加了停止使用可卡因的动机，并减少了线索诱导的渴望，与活跃的对照组相比，在注射后24小时。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中使用。在这些发现的基础上，该项目旨在研究氯胺酮是否会在临床环境中有益于有问题的酒精使用。我们将评估单次麻醉下剂量的氯胺酮(0.11 mg/kg在2分钟内，然后0.60 mg/kg在50分钟内)对40名接受动力增强疗法(MET)的非抑郁酒精依赖者的酒精依赖的影响。我们预测，与有效控制咪达唑仑相比，氯胺酮将显著减少重度饮酒天数的百分比。次要目标与氯胺酮对酒精相关的前额叶功能障碍的影响有关 或谷氨酸异常，如压力敏感、渴望、戒断、冲动、自我效能低下和注意力不集中。因此，我们的目标是以一种有能力为该领域做出重要贡献的方式来评估一种高度创新的干预措施。氯胺酮对这些结果的影响表明，短暂有效的谷氨酸能调制代表了一种可能的酒精依赖治疗策略，值得进一步研究。

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.