Brief Potent Glutamatergic Modulation: Applications for Cocaine Dependence

描述(申请人提供)：可卡因依赖仍然是一个严重的健康问题，缺乏有效的药物治疗。在这份K23以患者为导向的研究事业发展奖的申请书中，伊莱亚斯·达克瓦博士提出了一项全面的计划，旨在成为药物依赖创新治疗的独立研究人员。具体地说，这项建议将集中在麻醉下输注氯胺酮治疗可卡因依赖，氯胺酮是一种高亲和力的非竞争性N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂，最近作为一种新的抗抑郁策略出现。其抗抑郁作用的机制-调节前扣带回皮质(ACC)，增加大脑前额叶区域的神经可塑性-暗示氯胺酮可能在治疗可卡因依赖方面也有作用。前额叶功能障碍被认为与药物依赖的形成和维持高度相关，尤其是ACC功能障碍与觉醒、冲动和应激敏感性有关，以及与线索反应性和可卡因使用者复发风险的增加有关。谷氨酸系统的破坏被认为是这些临床上显著的前额叶功能损害的基础，通过调节谷氨酸的NMDAR拮抗被认为是解决这些缺陷的一种方法。然而，唯一被研究的特定拮抗剂美金刚在人类身上没有显示出效果。最近的研究表明，亚麻醉剂量的氯胺酮对人类大脑系统具有强大、独特和持续的活性，这表明它可能能够以一种美金刚无法观察到的方式恢复正常的大脑功能，并可能产生临床前和动物研究中使用NMDAR拮抗剂所预测的可卡因依赖的影响。因此，这项试验旨在通过一项随机、安慰剂对照试验，研究氯胺酮对新戒除可卡因依赖者复发风险(首次使用可卡因的时间)的影响，并探讨其在应激敏感性、专注性和冲动性方面的作用机制。即使在没有积极发现的情况下，拟议的项目也将通过阐明NMDAR封锁作为药物依赖治疗战略的作用来推动该领域的发展。此外，它还有助于更广泛地了解针对某些脆弱性，如压力敏感度和正念障碍，可能会如何影响成瘾。在他的导师(弗朗西斯·R·莱文博士)和导师(卡尔·哈特博士和桑杰·马修博士)的专业知识下从事这一领域的研究时，达克瓦博士将同时参与一项个性化的培训计划，以便在以下重要领域得到发展：1)人体实验室和临床试验研究的设计、方法学和后勤，2)高级生物统计学，3)负责任的研究进行，4)手稿准备，5)拨款撰写和拨款管理技能，以及6)行为和翻译神经生物学。总体而言，这一奖项将确保达克瓦博士成功地过渡到药物依赖创新治疗的独立研究员。

DESCRIPTION (provided by applicant): Cocaine dependence remains a significant health problem for which effective pharmacotherapy treatments are lacking. In this application for a K23 Mentored Patient Oriented Research Career Development Award, Dr. Elias Dakwar proposes a comprehensive plan towards becoming an independent researcher of innovative treatments for drug dependence. Specifically, this proposal will focus on treating cocaine dependence with sub-anesthetic infusions of ketamine, a high-affinity non-competitive N- methyl-D-aspartate receptor (NMDAR) antagonist, which has recently emerged as a novel antidepressant strategy. Purported mechanisms of its antidepressant action - modulation of the anterior cingulated cortex (ACC), increased neural plasticity in the prefrontal regions of the brain - suggest that ketamine may have a role in the treatment of cocaine dependence as well. Prefrontal dysfunction is believed to be highly associated with the development and maintenance of drug dependence, and ACC dysfunction in particular has been implicated in arousal, impulsivity, and stress sensitivity, as well as in cue reactivity and increased risk of relapse in cocaine users. Disruptions in the glutamate system are hypothesized to underlie these clinically significant impairments in prefrontal functioning, and NMDAR antagonism, via modulation of glutamate, has been proposed as a way to address these deficits. However, the only specific antagonist studied, memantine, failed to show an effect in humans. As recent studies demonstrate, the robust, unique and sustained activity of sub-anesthetic dose ketamine on human brain systems suggest that it may be able to restore normal brain function in a way not observed with memantine, and potentially produce the effects on cocaine dependence that preclinical and animal studies with NMDAR antagonists have been predicting. This trial therefore aims to investigate in a randomized, placebo-controlled trial the effect of ketamine on risk of relapse (time to first cocaine use) in newly abstinent cocaine dependent individuals, as well as to investigate mechanisms of action in regards to stress sensitivity, mindfulness, and impulsivity. Even in the absence of positive findings, the proposed project stands to advance the field by elucidating the role of NMDAR blockade as a treatment strategy for drug dependence. Also, it can contribute more generally to understanding how targeting certain vulnerabilities, such as stress sensitivity and mindfulness impairment, might impact addiction. While pursuing this line of research with the expertise of his mentor (Dr. Frances R. Levin) and preceptors (Drs. Carl Hart and Sanjay Mathew), Dr. Dakwar will concurrently engage in an individualized training program so as to develop in the following important areas: 1) human laboratory and clinical trial study design, methodology, and logistics, 2) advanced biostatistics, 3) responsible conduct of research, 4) manuscript preparation, 5) grant-writing and grant-management skills, and 6) behavioral and translational neurobiology. Overall, this award will ensure Dr. Dakwar's successful transition to an independent investigator of innovative treatments for drug dependence.