Mechanisms of the Nicotine Metabolism Effect on Tobacco Dependence

描述（由申请人提供）：既往研究表明，尼古丁代谢更快的吸烟者对戒烟治疗的戒烟率较低。尼古丁代谢率是戒烟最可靠的预测指标之一。这项建议的总体目标是阐明尼古丁代谢率影响烟草依赖的未知机制。这可能对了解特定戒烟药物的工作原理以及为特定吸烟者选择最佳药物具有重要意义。我们的研究将使用尼古丁代谢物比率（NMR）（尼古丁代谢物3 '羟基可替宁和可替宁之间的比率，由我们实验室开发和验证的测试）作为尼古丁代谢速率的简单且临床可行的生物标志物。我们假设代谢速率加快导致尼古丁从体内更快地消除，并且在吸烟间隔期间大脑对尼古丁的耐受性更快地消散，从而导致（1）更严重的尼古丁戒断症状和（2）剥夺后吸烟的更大主观奖励。这些影响将有助于解释为什么尼古丁代谢速率较快的吸烟者与代谢速率较慢的吸烟者相比，对戒烟治疗的反应较差。我们将探讨NMR与戒断、渴望和奖励的内在表型的关系，并假设这些因素可能是尼古丁代谢与烟草依赖和药物治疗戒烟率之间联系机制的中介。我们的研究设计使用了一个简短的（6小时）戒烟的间隔，然后是一个“奖励”香烟，以引起有关退出和奖励的主观反应。由于吸烟行为和尼古丁依赖的严重程度因种族和性别而异，我们还将比较非裔美国人与白色吸烟者以及男性与女性之间NMR与戒断和奖励之间的关系。次要分析将检查尼古丁半衰期是否介导观察到的NMR对主要应答指标的影响[已删除与CYP2A6基因分型相关的其他目的]。

DESCRIPTION (provided by applicant): Prior research indicates that smokers who metabolize nicotine more rapidly have lower quit rates in response to smoking cessation therapy. The rate of nicotine metabolism is one of the most robust predictors of abstinence. The overall goal of this proposal is to elucidate the as yet unknown mechanisms by which the rate of nicotine metabolism influences tobacco dependence. This could have important implications for understanding how particular smoking cessation medications work and in selecting the best medication for a particular smoker. Our studies will use the nicotine metabolite ratio (NMR) (the ratio between the nicotine metabolites 3'hydroxycotinine and cotinine, a test that was developed and validated by our laboratory) as a simple and clinically feasible biomarker for the rate of nicotine metabolism. We hypothesize that a faster rate of metabolism leads to faster elimination of nicotine from the body and a more rapid dissipation of brain tolerance to nicotine in the interval between cigarettes, leading in turn to (1) more severe nicotine withdrawal symptoms and (2) greater subjective reward from the cigarette smoked following deprivation. These effects would help to explain why smokers with faster rates of nicotine metabolism have a poorer response to smoking cessation therapy when compared to those with slower rates of metabolism. We will explore the relationship of the NMR to the endophenotypes of withdrawal, craving and reward, with the assumption that these factors are likely intermediaries for the mechanism linking nicotine metabolism to tobacco dependence and smoking cessation rates with pharmacotherapy. Our study design uses a brief (6 hour) interval of smoking abstinence followed by a "reward" cigarette to elicit the subjective responses relating to withdrawal and reward. Because smoking behavior and severity of nicotine dependence vary by race and sex we will also compare the relationship between NMR and withdrawal and reward in African American vs. white smokers and in men vs. women. Secondary analyses will examine whether nicotine half-life mediates the observed effects of NMR on primary response measures [additional aim relating to CYP2A6 genotyping has been eliminated].