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一个重要目标。我们对氯胺酮的初步研究表明，氯胺酮是一种谷氨酸调节剂，具有有效的前额叶效应，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。我们发现，在输注24小时后，与主动对照组相比，亚麻醉氯胺酮显著增加了主动吸毒者停止使用可卡因的动机，减少了线索诱导的渴望。一项正在进行的临床试验也表明氯胺酮在门诊成瘾治疗中是可行的。在这些发现的基础上，该项目旨在研究氯胺酮是否会对临床环境中的问题酒精使用有益。我们将评估单次亚麻醉剂量氯胺酮（0.11 mg/kg 2分钟，随后0.60 mg/kg 50分钟）对40名从事动机增强疗法（MET）的非抑郁酒精依赖个体的酒精依赖的影响。我们预测，与主动对照咪达唑仑相比，氯胺酮将显著减少重度饮酒天数的百分比。次要目的涉及氯胺酮对涉及前额叶功能障碍的酒精相关缺陷的影响

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.