Neuropharmacology of Cue-Induced Nicotine Relapse

提示诱导尼古丁复吸的神经药理学

• 批准号: 6920396
• 负责人: XIU LIU
• 金额: $ 25.99万
• 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/6920396
• 关键词: behavior test; behavioral /social science research tag; biological models; conditioning; craving; cues; drug addiction; laboratory rat; motivation; neuropharmacology; nicotine; relapse /recurrence; substance abuse related behavior; tobacco abuse

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。戒烟后再次吸烟是尼古丁成瘾的主要特征之一。每年只有大约3%的吸烟者成功地保持戒烟。戒断后极易复发，这对尼古丁成瘾的治疗提出了巨大的挑战。对成瘾行为的持续存在和戒断后复发的高风险的一种解释是条件反射假说，这是基于对复发通常与暴露于与药物相关的环境刺激有关的观察。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，吃完一顿饭，喝酒精饮料，和吸烟的朋友在一起，喝咖啡，看晨报）成为诱发主观状态的线索，从而引发渴望，寻求毒品的行为和重新使用尼古丁。这些与尼古丁相关的线索在日常生活中的普遍存在表明，与其他药物滥用相比，线索可能在尼古丁成瘾中发挥更大的作用。尽管人体研究表明，与尼古丁使用相关的环境刺激会在戒烟者中产生生理和主观变化，但尼古丁相关线索在引发复发中的重要性却很少得到实验关注。本实验采用复吸动物模型，旨在研究与药物线索暴露相关的尼古丁寻求行为的环境和神经药理学基础。动物模型将采用一种反应恢复程序，动物最初被训练成通过按压操作性条件反射室中的杠杆来自我管理尼古丁，然后通过不给药来消除药物增强的行为。在尼古丁强化行为消失后，尼古丁相关刺激（即提示）、尼古丁本身（即启动）以及两者恢复尼古丁寻求的能力是确定的。近年来，越来越多地使用这些恢复程序，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。本实验将探讨尼古丁相关线索、尼古丁启动及其组合在复发操作性反应-恢复模型中的动机意义，并确定尼古丁线索、尼古丁启动及其组合对多巴胺能和尼古丁神经传递的药理拮抗作用是否敏感。拟议研究的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。结果不仅将为未来的临床前研究奠定基础，而且还将有助于设计未来的试验，以防止人类复发。