Motivation for Cocaine and Non-Drug Reinforcers: Targeting Glutamate Homeostasis

可卡因和非药物强化剂的动机：以谷氨酸稳态为目标

• 批准号: 8633724
• 负责人: William Walton Stoops
• 金额: $ 20.82万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633724
• 关键词: Abstinence; Acetylcysteine; Acute; American; Area; Attention; Attenuated; Automobile Driving; Basic Science; Behavior; Brain; Ceftriaxone; Chronic; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Cocaine Users; Cognitive; Complement; Complex; Cues; Cystine; Data; Decision Making; Diagnostic; Disease; Dose; Drug Use Disorder; Glutamate Transporter; Glutamates; Goals; Homeostasis; Human; Laboratories; Left; Link; Maintenance; Measures; Motivation; Neuropharmacology; Neurosciences Research; Oral; Outcome; Pattern; Performance; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Placebos; Population; Pre-Clinical Model; Prevalence; Public Health; Relative (related person); Reporting; Research; Role; Safety; Sampling; Schedule; Self Administration; System; Testing; Translating; United States; cocaine exposure; cocaine use; flexibility; human subject; improved; insight; meetings; non-drug; pre-clinical; pre-clinical research; preclinical study; public health relevance; reinforcer; research study; restoration; therapy development; transmission process

ABSTRACT Cocaine is the most commonly used illicit stimulant in the United States. Despite great strides in our understanding of the neuropharmacological underpinnings of cocaine addiction in the preclinical arena, the number of cocaine users in the United States has remained relatively stable in recent years, indicating that more clinical research is necessary to translate these findings to humans in an attempt to develop more effective means of reducing cocaine use. Emerging data suggest that perturbations in glutamate transmission following cocaine use (i.e., disrupted glutamate homeostasis) contribute to the maladaptive pattern of drug taking characterized by cocaine addiction. Specifically, preclinical studies indicate that cocaine exposure results in increased motivation to take cocaine and decreased drive for non-drug reinforcers. This change in reinforcer salience corresponds with complex neuropharmacological changes in the glutamate system. Whereas preclinical data suggest that targeting glutamate systems, specifically restoring glutamate homeostasis, reduces drug reinforcer salience, this research area remains relatively unexplored in humans. Some initial studies suggest that n-acetylcysteine pretreatment normalizes glutamate levels in cocaine users and that n-acetylcysteine maintenance attenuates desire for cocaine and attention to cocaine cues in abstinent cocaine-dependent subjects. Whether restoration of glutamate homeostasis impacts motivation for drug relative to non-drug reinforcers remains to be determined in humans. The research proposed here will demonstrate that restoration of glutamate homeostasis reduces motivation to take cocaine and increases motivation to obtain a non-drug alternative reinforcer (i.e., money) in cocaine-dependent humans using progressive-ratio schedules of reinforcer availability, which are an accepted means to measure motivation. The use of concurrent progressive-ratio schedules of drug and non-drug reinforcer availability will allow inferences to be made about the influence of restored glutamate homeostasis on motivation to obtain these two types of reinforcers. Cognitive tasks that assess domains relating to reinforcer choice also will be included to complement the self-administration outcomes. This study will translate findings from preclinical research and provide the initial clinical evidence that restoration of glutamate homeostasis shifts reinforcer salience away from drug reinforcers towards non-drug reinforcers in active cocaine users. Outcomes of the experiment will not only contribute to our understanding of the clinical neuropharmacology of cocaine addiction, they also can be used to guide development of treatments for cocaine use disorders.

摘要 可卡因是美国最常用的非法兴奋剂。尽管我们在这方面取得了很大的进步， 了解可卡因成瘾的神经药理学基础在临床前竞技场， 近年来，美国可卡因使用者的人数保持相对稳定，这表明， 有必要进行更多的临床研究，以将这些发现转化为人类， 减少可卡因使用的有效方法。新出现的数据表明，谷氨酸传输的扰动 在可卡因使用之后（即，破坏的谷氨酸体内平衡）有助于药物的适应不良模式 以可卡因成瘾为特征的服用。具体来说，临床前研究表明， 导致服用可卡因的动机增加，而非药物成瘾者的动力减少。的这种变化 大脑的显著性与谷氨酸系统中复杂的神经药理学变化相对应。 然而临床前数据表明，靶向谷氨酸系统，特别是恢复谷氨酸 然而，由于体内平衡，减少药物代谢的显著性，该研究领域在人类中仍然相对未被探索。 一些初步研究表明，N-乙酰半胱氨酸预处理使可卡因使用者的谷氨酸水平正常化 并且N-乙酰半胱氨酸维持会减弱戒断者对可卡因的渴望和对可卡因线索的注意力， 可卡因依赖者谷氨酸稳态的恢复是否影响药物的动机 相对于非药物代谢物，在人体中的作用仍有待确定。本文提出的研究将 证明谷氨酸体内平衡的恢复减少了服用可卡因的动机， 获得非药物替代药物的动机（即，钱）在可卡因依赖的人使用 累进比率的可用性，这是一个公认的手段来衡量动机。的 同时使用药物和非药物治疗可用性的累进比率时间表将允许推断 关于恢复谷氨酸稳态对获得这两种类型的动机的影响， 咖啡机。评估与选择者选择有关的领域的认知任务也将包括在内， 补充自我管理的成果。这项研究将转化临床前研究的结果， 提供了初步的临床证据，证明谷氨酸体内平衡的恢复使大脑的显著性消失， 从吸毒者转向非吸毒者。实验的结果将 不仅有助于我们理解可卡因成瘾的临床神经药理学， 用于指导开发可卡因使用障碍的治疗方法。