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指导的以患者为导向的研究职业发展奖的申请中，Elias Dakwar博士提出了一项全面的计划，旨在成为药物依赖创新疗法的独立研究人员。具体而言，该提案将重点关注通过氯胺酮的亚麻醉输注治疗可卡因依赖，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，最近已成为一种新型抗抑郁策略。据称其抗抑郁作用的机制-前扣带皮层（ACC）的调制，增加大脑前额叶区域的神经可塑性-表明氯胺酮也可能在治疗可卡因依赖中发挥作用。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ACC功能障碍与觉醒、冲动和应激敏感性以及可卡因使用者的线索反应性和复发风险增加有关。假设谷氨酸系统的破坏是这些临床上显著的前额叶功能障碍的基础，并且已经提出通过调节谷氨酸的NMDAR拮抗作用作为解决这些缺陷的一种方式。然而，研究的唯一特异性拮抗剂美金刚胺未能在人类中显示出效果。最近的研究表明，亚麻醉剂量氯胺酮对人脑系统的稳健、独特和持续活性表明，它可能能够以美金刚未观察到的方式恢复正常脑功能，并可能对可卡因依赖产生影响，这是NMDAR拮抗剂的临床前和动物研究所预测的。因此，本试验旨在通过一项随机、安慰剂对照试验研究氯胺酮对新近戒断可卡因依赖者复发风险（至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，它可以更普遍地帮助理解针对某些脆弱性，如压力敏感性和正念障碍，可能会影响成瘾。在与他的导师（博士弗朗西斯R。莱文）和preceptors（卡尔哈特和桑杰马修博士），达克瓦尔博士将同时从事个性化的培训计划，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，方法学和后勤，2）先进的生物统计学，3）负责任的研究行为，4）手稿准备，5）赠款写作和赠款管理技能，行为和转化神经生物学。总的来说，这一奖项将确保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.