Brief Potent Glutamatergic Modulation: Applications for Cocaine Dependence

描述（由申请人提供）：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K23指导患者导向研究职业发展奖的申请中，Elias Dakwar博士提出了一个全面的计划，成为药物依赖创新治疗的独立研究人员。具体来说，本建议将重点放在通过亚麻醉输注氯胺酮治疗可卡因依赖上，氯胺酮是一种高亲和力非竞争性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药物出现。据称其抗抑郁作用的机制——调节前扣带皮层（ACC），增加大脑前额叶区域的神经可塑性——表明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发展和维持高度相关，特别是前扣带功能障碍与可卡因使用者的觉醒、冲动、压力敏感性以及线索反应性和复发风险增加有关。谷氨酸系统的破坏被认为是这些临床意义上的前额叶功能损伤的基础，而NMDAR拮抗，通过谷氨酸的调节，被认为是解决这些缺陷的一种方法。然而，所研究的唯一特异性拮抗剂美金刚在人体中没有显示出效果。最近的研究表明，亚麻醉剂量氯胺酮对人脑系统的强大、独特和持续的活性表明，它可能能够以一种美金刚未观察到的方式恢复正常的脑功能，并可能产生NMDAR拮抗剂的临床前和动物研究所预测的对可卡因依赖的影响。因此，本试验旨在通过一项随机、安慰剂对照试验来研究氯胺酮对新戒断可卡因依赖个体复发风险（首次使用可卡因的时间）的影响，并研究其在压力敏感性、正念和冲动性方面的作用机制。即使没有积极的发现，拟议的项目也将通过阐明NMDAR阻断作为药物依赖治疗策略的作用来推进该领域。此外，它可以更广泛地帮助理解如何针对某些弱点，如压力敏感性和正念障碍，可能会影响成瘾。在他的导师（Frances R. Levin博士）和导师(dr。（Carl Hart和Sanjay Mathew）， Dakwar博士将同时参与一个个性化的培训计划，以便在以下重要领域发展：1)人类实验室和临床试验研究设计，方法和后勤，2)高级生物统计学，3)负责任的研究行为，4)手稿准备，5)拨款写作和拨款管理技能，以及6)行为和转化神经生物学。总的来说，该奖项将确保Dakwar博士成功过渡到药物依赖创新治疗的独立研究者。

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.