NOVEL METHODS TO EXPLORE MECHANISMS OF COCAINE ABUSE

探索可卡因滥用机制的新方法

• 批准号: 3214938
• 负责人: George F. Koob
• 金额: $ 20.96万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3214938
• 关键词: behavior test; behavioral extinction; cocaine; disease /disorder model; dopamine; drug addiction; electrophysiology; extracellular; laboratory rat; microdialysis; neuropharmacology; neurophysiology; neurotransmitter transport; nucleus accumbens; reinforcer; relapse /recurrence; self medication; serotonin; single cell analysis; synapses

This proposal was generated in response to RFA DA-93-01 and is designed to establish in vivo neurochemical and electrophysiological correlates of cocaine-seeking behaviors that can then be used to design potential novel treatment drugs for cocaine dependence. These animal models are designed to permit assessment of the neurochemical and physiological basis of cocaine reward magnitude, strength of cocaine-seeking behaviors ("craving"), and the "propensity to relapse" in limited access and the dependent state. Behavioral parameters of various cocaine-seeking behaviors will be established in rats with different histories of cocaine preexposure. Specifically, cocaine-seeking behaviors of rats with a history of daily limited-access cocaine self-administration will be compared to those exhibited by rats given extended access to cocaine. The proposed studies will examine whether the behavioral manifestations of cocaine "craving" are subserved by the same or different, neuropharmacological substrates as the acute reinforcing effects of cocaine. To accomplish these goals, behavioral parameters of responding for cocaine under different reinforcement contingencies will be established in rats after episodes of extended-access cocaine self- administration using progressive ratio, and multiple schedules. Repeated extinction and spontaneous recovery tests in the presence and absence of environmental cues associated with cocaine availability will provide information about the persistence of cocaine-seeking behaviors. Neurochemical correlates of these behavioral measures will be established using intracranial microdialysis for dopamine and serotonin in various forebrain sites. Neurophysiological correlates of these behavioral methods will be measured using extracellular recording techniques in freely-moving rats at various forebrain sites. Novel pharmacological therapies will be developed by determining effective pharmacological means of reversing the neurochemical (in vivo microdialysis) and electrophysiological (extracellular recording) changes associated with these various components of cocaine-seeking behavior in both limited-access and dependent animals. Treatments effective in modifying these neuropharmacological events will then be tested in the behavioral paradigms for potential pharmacotherapeutic action. These studies will provide important, presently unavailable insights into the neuropharmacological substrate(s) mediating specific cocaine-seeking behaviors as well as information about the relationship between self-administration history and cocaine-seeking behaviors. Finally, the work in this proposal will provide a novel means for the development of specific and novel drugs with therapeutic potential for treating or preventing cocaine abuse and dependence.

本提案是根据RFA DA-93-01生成的，旨在 在体内建立神经化学和电生理的相关性 寻找可卡因的行为，然后可以用来设计潜在的小说 治疗可卡因依赖的药物。这些动物模型是设计的 以允许评估神经化学和生理基础 可卡因奖赏程度、寻找可卡因行为强度 (“渴望”)，以及“复发倾向”在有限的访问和 从属状态。不同类型可卡因寻求者的行为参数 不同可卡因吸毒史的大鼠将建立行为 预曝光。具体地说，应激大鼠的可卡因寻找行为。 每日限制使用可卡因自我管理的历史将是 与延长可卡因接触时间的大鼠相比。这个 拟议的研究将检查是否有行为表现 可卡因的“渴望”由相同或不同的， 神经药理作用底物的急性增强作用 可卡因。为了实现这些目标，响应的行为参数 对于可卡因在不同加固情况下的意外情况将是 在大鼠多次长时间吸食可卡因后建立 使用累进比率和多个时间表进行管理。重复 在存在和不存在的情况下的灭绝和自发恢复试验 与可卡因可获得性相关的环境线索将提供 关于持续吸食可卡因行为的信息。 这些行为测量的神经化学关联将被建立 应用颅内微透析治疗各种疾病的多巴胺和5-羟色胺 前脑部位。这些行为方法的神经生理学相关性 将使用细胞外记录技术在自由移动中进行测量 大鼠在不同的前脑部位。新的药理疗法将是 通过确定有效的药理手段来逆转 神经化学(体内微透析)和电生理学 (细胞外记录)与这些不同组件相关的变化 在接触受限和依赖的动物中寻找可卡因的行为。 有效地改变这些神经药理学事件的治疗方法将 然后在行为范式中测试潜在的 药物治疗作用。这些研究将提供重要的、 目前对神经药理学底物缺乏深入了解(S) 调解特定的可卡因寻找行为以及关于 自我给药史与吸食可卡因的关系 行为。最后，本提案中的工作将提供一种新的手段 开发具有治疗潜力的特效药和新药 用于治疗或防止可卡因滥用和依赖。