Effectiveness of Varenicline: Testing Individual Differences

更好地理解烟草使用的神经生物学中的个体差异是发展不可或缺的 更有效的烟草干预措施。了解这些个体差异将有助于匹配 具有特定生物脆弱性的个人(例如，改变尼古丁受体功能的基因变异)， 针对这种脆弱性的干预(例如，针对尼古丁受体功能的药物，如 Varenicline)。我们以前的研究清楚地表明了特定的遗传变异在基因中的关键作用。 (CHRNA4)，它编码尼古丁受体的第4亚基。这项拟议的研究将扩展我们的 之前的工作是测试这种基因变异是否会影响大脑对吸烟线索的反应 影响了伐伦克林的临床疗效。具体地说，第一个目标是确定功能 CHRNA4基因单核苷酸多态(SNP)影响吸烟和吸烟的急性效应 影响中皮质边缘对吸烟提示的反应的激活。第二个目标是复制 发现varenicline增加了戒断率，并确定了预测治疗的基于大脑的指标 结果。第三个目的是确定CHRNA4 SNP是否缓和了varenicline对 禁欲。为了实现这些目标，216名寻求治疗的吸烟者将参加为期12周的安慰剂治疗 瓦伦尼克林的对照试验，基线为神经影像评估，行为评估为 基线、2周、6周和12周，以及6个月的随访。关于遗传变异的拟议研究 预测对varenicline的反应预计将具有重大的临床意义。

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 ¿4 subunit of the ¿4¿2 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.