Neuropharmacology of Cue-Induced Nicotine Relapse

提示诱导尼古丁复吸的神经药理学

• 批准号: 7060424
• 负责人: XIU LIU
• 金额: $ 21.75万
• 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/7060424
• 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(申请人提供)：烟草使用是一种慢性复吸障碍。戒烟后反复恢复使用烟草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状态。戒烟后很容易复发，这给尼古丁成瘾的治疗带来了巨大的挑战。对戒毒后持续存在的成瘾行为和高复发风险的一种解释是条件性假说，该假说是基于观察到的复发通常与接触与药物相关的环境刺激有关。随着时间的推移，在成千上万次这样的配对之后，与吸烟相关的刺激(例如，吃完一顿饭，喝酒精饮料，和吸烟的朋友一起，喝咖啡，读早报)成为引发主观状态的线索，可能会引发渴望、寻求毒品的行为和重新开始使用尼古丁。这些与尼古丁相关的线索在日常生活中无处不在，这表明与其他滥用药物相比，线索可能在尼古丁成瘾中发挥更大的作用。尽管人类研究表明，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，但与尼古丁相关的线索在触发复发方面的重要性几乎没有受到实验的关注。拟议的实验是使用复发的动物模型设计的，以调查与接触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。动物模型将采用一种反应恢复程序，在这种程序中，动物最初被训练通过按下操作条件反应室中的杠杆来自我给药尼古丁，然后通过停止给药来消除药物强化的行为。在尼古丁强化的行为消失后，确定尼古丁相关刺激(即线索)、尼古丁本身(即引发)以及两者恢复尼古丁寻找的能力。近年来，这些恢复程序的使用越来越多，它们提供了关于吸毒(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。这些实验将表征尼古丁相关线索、尼古丁启动及其组合在复发的操作型反应-恢复模型中的激励意义，并确定尼古丁提示、尼古丁启动及其组合的反应恢复效应是否对多巴胺能和尼古丁神经传递的药理拮抗敏感。建议的研究结果将为尼古丁相关线索在重新启动尼古丁寻找行为中的作用提供重要的基础信息。研究结果不仅将为未来的临床前研究奠定基础，还将有助于设计未来防止人类复发的试验。