Effectiveness of Varenicline: Testing Individual Differences

描述(由申请人提供)：更好地了解烟草使用的神经生物学方面的个体差异是开发更有效的烟草干预措施不可或缺的一部分。了解这些个体差异将有助于将具有特定生物脆弱性(例如，改变尼古丁受体功能的遗传变异)的个人与针对该脆弱性的干预措施(例如，针对尼古丁受体功能的药物，如varenicline)进行匹配。我们以前的研究清楚地表明了编码1422尼古丁受体14亚基的基因(CHRNA4)中特定的遗传变异的关键作用。这项拟议的研究将通过测试这种基因变异是否影响大脑对吸烟线索的反应以及影响varenicline的临床效果来扩展我们之前的工作。具体地说，第一个目的是确定CHRNA4基因的功能性单核苷酸多态(SNP)是否影响吸烟的急性效应，以及是否影响对吸烟提示的中皮质边缘激活。第二个目标是重复这一发现，即varenicline增加了禁欲，并确定了预测治疗结果的基于大脑的措施。第三个目的是确定CHRNA4 SNP是否缓和了varenicline对戒酒的影响。为了实现这些目标，216名寻求治疗的吸烟者将参加一项为期12周的Varenicline安慰剂对照试验，在基线、2、6和12周以及6个月的随访中进行神经成像评估和行为评估。这项关于遗传变异的研究预测了对varenicline的反应，预计将具有重要的临床意义。 公共卫生相关性： 尽管我们对人类基因组的理解取得了快速进展，但对影响烟草依赖的病因和治疗的遗传因素的识别尚未实现。这项研究旨在确定与人们对烟草的反应方式有关的特定基因变异，并确定它们与烟草依赖的关系。这项研究还将测试这些基因变异是否可以预测目前最有效的戒烟药物varenicline的疗效。我们对影响烟草依赖病因学的遗传因素和神经生物学机制的了解的改善，预计将对新的预防和治疗方法产生影响。

DESCRIPTION (provided by applicant): A greater understanding of individual differences in the neurobiology of tobacco use is integral to developing more effective tobacco interventions. Understanding these individual differences would facilitate matching individuals with a specific biological vulnerability (e.g., genetic variation that alters nicotine receptor function), to an intervention that targets that vulnerability (e.g., a medication that targets nicotinic receptor function, like varenicline). Our previous studies clearly indicate the critical role of specific genetic variation in the gene (CHRNA4) that codes for the 14 subunit of the 1422 nicotinic receptor. This proposed research will extend our previous work by testing whether this genetic variation influences brain activation in response to smoking cues and influences the clinical effects of varenicline. Specifically, the first aim is to determine whether a functional single nucleotide polymorphism (SNP) in the CHRNA4 gene influences the acute effects of smoking and influences mesocorticolimbic activation in response to smoking cues. The second aim is to replicate the finding that varenicline increases abstinence and identify brain based measures that predict treatment outcome. The third aim is to determine whether the CHRNA4 SNP moderates the effects of varenicline on abstinence. To accomplish these aims, 216 treatment seeking smokers will participate in a 12 week, placebo controlled trial of varenicline with a neuroimaging assessment at baseline and behavioral assessments at baseline, 2, 6, and 12 weeks and a 6 month follow-up. The proposed research on genetic variation that predicts responses to varenicline is expected to have significant clinical implications. PUBLIC HEALTH RELEVANCE: Despite rapid advances in our understanding of the human genome, the identification of genetic factors that influence the etiology and treatment of tobacco dependence has yet to materialize. This research is designed to identify specific genetic variations that are related to how people respond to tobacco and identify how they are related to tobacco dependence. This research will also test whether these genetic variations predict the effectiveness of varenicline, which is currently the most effective medication for smoking cessation. Improvements in our understanding of genetic factors and neurobiological mechanisms that influence the etiology of tobacco dependence is expected to have implications for new prevention and treatment approaches.