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个体差异对于制定更有效的烟草干预措施是不可或缺的。了解这些个体差异将有助于将个体与特定的生物脆弱性（例如，改变尼古丁受体功能的遗传变异）相匹配，并针对该脆弱性进行干预（例如，针对尼古丁受体功能的药物，如伐尼克兰）。我们之前的研究清楚地表明，编码1422烟碱受体14亚基的基因（CHRNA4）的特定遗传变异具有关键作用。这项拟议的研究将扩展我们之前的工作，通过测试这种遗传变异是否会影响大脑对吸烟线索的反应，以及是否会影响伐尼克兰的临床效果。具体来说，第一个目的是确定CHRNA4基因的功能性单核苷酸多态性（SNP）是否影响吸烟的急性效应，并影响吸烟提示时中皮质边缘的激活。第二个目标是复制伐尼克兰增加戒断的发现，并确定预测治疗结果的基于大脑的措施。第三个目的是确定CHRNA4 SNP是否能调节伐尼克兰对戒断的影响。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周的安慰剂对照试验，在基线时进行神经影像学评估，在基线、2周、6周和12周进行行为评估，并进行6个月的随访。提出的基因变异预测对伐尼克兰的反应的研究预计具有重要的临床意义。

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.