Brief Potent Glutamatergic Modulation: Applications for Cocaine Dependence

简短有效的谷氨酸调节：可卡因依赖的应用

• 批准号: 8710132
• 负责人: Elias Dakwar
• 金额: $ 18.62万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710132
• 关键词: Abstinence; Address; Affinity; Anesthetics; Animals; Anterior; Antidepressive Agents; Area; Arousal; Award; Behavioral; Biometry; Brain; Brain region; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Cocaine Users; Cues; Data; Development; Dissociation; Dose; Drug Addiction; Drug usage; Endocrine; Ensure; France; Functional disorder; Future; Glutamates; Goals; Grant; Health; Homeostasis; Human; Impairment; Impulsivity; Individual; Informal Social Control; Infusion procedures; Inpatients; Intervention; Ketamine; Laboratories; Laboratory Procedures; Lead; Logistics; Maintenance; Manuscripts; Measures; Memantine; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; N-Methyl-D-Aspartate Receptors; Neurobiology; Neuronal Plasticity; Outpatients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Placebos; Preparation; Public Health; Questionnaires; Randomized; Relapse; Research; Research Design; Research Personnel; Risk; Role; Stress; System; Testing; Therapeutic; Time; Training; Training Programs; Work; Writing; addiction; base; career; cingulate cortex; clinically significant; cocaine use; cue reactivity; disorder later incidence prevention; experience; improved; innovation; mindfulness; novel; operation; pre-clinical; randomized placebo controlled trial; response; responsible research conduct; skills; stressor; synaptogenesis; treatment effect; treatment response; treatment strategy; week trial

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.

描述（由申请人提供）：可卡因依赖仍然是一个重要的健康问题，缺乏有效的药物治疗。在此申请K23指导的以患者为导向的研究职业发展奖中，Elias Dakwar博士提出了一项全面的计划，以成为毒品依赖创新治疗的独立研究人员。具体而言，该建议将集中于治疗可卡因依赖性，并使用氯胺酮的亚动理输注（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），最近已成为一种新型的抗抑郁药策略。据称其抗抑郁作用的机制 - 对前扣带皮层（ACC）的调节，大脑前额叶区域的神经可塑性增加 - 表明氯胺酮也可能在可卡因依赖性治疗中起作用。据信，前额叶功能障碍与药物依赖性的发展和维持高度相关，特别是ACC功能障碍与唤醒，冲动性和压力敏感性有关，以及可卡因使用者中的提示反应性和增加的复发风险。假设谷氨酸系统中的破坏是前额叶功能中这些临床上显着障碍的基础，并且已经提出了通过调节谷氨酸的NMDAR拮抗作用，作为解决这些缺陷的一种方式。但是，唯一研究的特定拮抗剂是纪念碑，未能显示出对人类的影响。正如最近的研究所表明的那样，亚手提剂量酮酮对人脑系统的稳健，独特和持续的活性表明，它可能能够以未观察到的美容剂观察到的方式恢复正常的脑功能，并有可能对可卡因依赖性产生对可卡因依赖性的影响，而抗可卡因和NMDAR拮抗剂的抗可卡因依赖性已经预测了。因此，该试验的目的是在一项随机的安慰剂对照试验中调查氯胺酮对新戒烟可卡因依赖性个体复发风险（首次可卡因使用的时间）的影响，以及调查在压力敏感性，正念和正念和冲动性方面的作用机制。即使在没有积极发现的情况下，提议的项目也将通过阐明NMDAR封锁作为药物依赖的治疗策略的作用来推进该领域。同样，它可以更普遍地了解针对某些漏洞（例如压力敏感性和正念障碍）如何影响成瘾。在以他的导师（Frances R. Levin博士）和主持人（Carl Hart博士和Sanjay Mathew）的专业知识进行这一研究的同时，Dakwar博士将同时参与一个个性化的培训计划，以在以下重要领域中发展，以便在以下重要领域中发展：1）人类实验室和临床试验研究，方法和物流，并构成了5）范围，2）高级生物学，3），3）4），3），3）4）4）以及授予管理技能，以及6）行为和转化神经生物学。总体而言，该奖项将确保达克瓦（Dakwar）博士成功地过渡到独立的药物依赖治疗方法。