Neuropharmacology of Cue-Induced Nicotine Relapse

提示诱导尼古丁复吸的神经药理学

• 批准号: 7214650
• 负责人: XIU LIU
• 金额: $ 21.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214650
• 关键词: Abstinence; Addictive Behavior; Alcohol consumption; Animal Model; Animals; Attention; Behavior; Characteristics; Chronic; Cocaine; Coffee; Condition; Cues; Daily; Data; Disease; Drug Delivery Systems; Exposure to; Extinction (Psychology); Friends; Future; Goals; Human; Life; Modeling; Nature; Neurobiology; Neuropharmacology; Newspapers; Nicotine; Nicotine Dependence; Operant Conditioning; Pharmaceutical Preparations; Physiological; Play; Procedures; Rattus; Reading; Recurrence; Relapse; Risk; Role; Self Administration; Self-Administered; Smoke; Smoker; Stimulus; Testing; Time; Tobacco use; Training; United States; addiction; base; conditioning; craving; design; drinking; drug of abuse; drug seeking behavior; human study; neurotransmission; preclinical study; prevent; reinforced behavior; research study; response

DESCRIPTION (provided by applicant): Tobacco use is a chronic relapsing disorder. Recurrent resumption of tobacco use after abstinence is one of the principal characteristics of nicotine addiction. Only approximately 3% of smokers successfully remain abstinent each year. The very high vulnerability to relapse following abstinence presents a formidable challenge for the treatment of nicotine addiction. One explanation for the persistence of addictive behavior and high risk of relapse after abstinence is the conditioning hypothesis, which is based on the observations that relapse is often associated with exposure to drug-related environmental stimuli. Over time, and after thousands of such pairings, the smoking-related stimuli (e.g., finishing a meal, the consumption of alcoholic beverages, being with friends who smoke, drinking coffee, reading the morning newspaper) become cues that elicit subjective states that can trigger craving, drug-seeking behavior and the resumption of nicotine use. The pervasive nature of these nicotine-associated cues in daily life suggests that cues might play a bigger role in nicotine addiction compared to other drugs of abuse. Although human studies have shown that environmental stimuli associated with nicotine use produce physiological and subjective changes in abstinent smokers, the significance of nicotine-related cues in triggering relapse has received little experimental attention. The proposed experiments are designed using an animal model of relapse to investigate the environmental and neuropharmacological bases of nicotine-seeking behavior associated with exposure to drug cues. The animal model will employ a response-reinstatement procedure where animals are initially trained to self-administer nicotine by pressing a lever in operant conditioning chambers and then the drug-reinforced behavior is extinguished by withholding the drug delivery. After extinction of the nicotine-reinforced behavior, the ability of nicotine-related stimuli (i.e., cues), nicotine itself (i.e., priming), and both to reinstate nicotine-seeking is determined. There has been an increasing use of these reinstatement procedures in recent years, and they have provided very important information on the neurobiological bases of drug (mainly cocaine and alcohol) use and relapse. The proposed experiments will characterize the motivational significance of nicotine-associated cues, nicotine priming, and their combination in an operant response-reinstatement model of relapse and determine whether the response-reinstating effects of nicotine cues, nicotine priming and their combination are sensitive to pharmacological antagonism of dopaminergic and nicotinic neurotransmission. The results of the proposed studies will provide important basic information on the role of nicotine-associated cues in the re-initiation of nicotine-seeking behavior. Results will not only lay the groundwork for future preclinical studies, but also will be useful in designing future trials to prevent relapse in humans.

描述（由申请人提供）：烟草使用是一种慢性复发性疾病。戒烟后反复恢复烟草使用是尼古丁成瘾的主要特征之一。每年只有大约3%的吸烟者成功戒烟。戒烟后极易复发，这对尼古丁成瘾的治疗提出了严峻的挑战。戒断后成瘾行为持续存在和复发风险高的一种解释是条件反射假说，该假说基于复发通常与暴露于与药物相关的环境刺激有关的观察结果。随着时间的推移，在数千次这样的配对之后，与吸烟相关的刺激（例如，吃完饭、喝酒精饮料、与吸烟的朋友在一起、喝咖啡、阅读晨报）成为诱发主观状态的线索，这些主观状态可引发渴望、寻求药物行为和恢复尼古丁使用。这些尼古丁相关线索在日常生活中的普遍性表明，与其他滥用药物相比，这些线索可能在尼古丁成瘾中发挥更大的作用。虽然人类研究表明，与尼古丁使用相关的环境刺激会导致戒烟者的生理和主观变化，但尼古丁相关线索在触发复吸中的重要性几乎没有得到实验关注。所提出的实验设计使用复发的动物模型来调查与暴露于药物线索相关的尼古丁寻求行为的环境和神经药理学基础。动物模型将采用反应-恢复程序，其中动物最初接受训练，通过按下操作性条件反射室中的杠杆进行尼古丁自我给药，然后通过停止给药消除药物强化行为。在尼古丁强化行为消失后，尼古丁相关刺激的能力（即，线索），尼古丁本身（即，引发），并且确定两者恢复尼古丁寻求。近年来，这些恢复程序的使用越来越多，它们提供了关于药物（主要是可卡因和酒精）使用和复发的神经生物学基础的非常重要的信息。拟议的实验将尼古丁相关的线索，尼古丁引发，以及它们的组合在复发的操作性反应恢复模型的动机意义的特征，并确定是否尼古丁线索，尼古丁引发和它们的组合的反应恢复效果是敏感的多巴胺能和烟碱神经传递的药理拮抗作用。这些研究结果将为尼古丁相关线索在重新启动尼古丁寻求行为中的作用提供重要的基础信息。结果不仅为未来的临床前研究奠定了基础，而且对设计未来的试验以预防人类复发也很有用。