Effectiveness of Varenicline: Testing Individual Differences

更好地理解烟草使用神经生物学中的个体差异是发展烟草使用神经生物学不可或缺的一部分。 更有效的烟草干预措施。了解这些个体差异有助于匹配 具有特定生物脆弱性的个体（例如，改变尼古丁受体功能的遗传变异）， 针对该漏洞的干预（例如，一种针对烟碱受体功能的药物， varenicline）。我们以前的研究清楚地表明了基因中特定遗传变异的关键作用 编码<$4 <$2烟碱受体<$4亚基的CHRNA 4。这项研究将扩大我们的 通过测试这种遗传变异是否会影响大脑对吸烟暗示的反应， 影响伐尼克兰的临床疗效。具体而言，第一个目标是确定是否有一个功能 CHRNA 4基因的单核苷酸多态性（SNP）影响吸烟的急性效应， 影响中皮质边缘激活响应吸烟线索。第二个目标是复制 发现伐尼克兰增加了禁欲，并确定了预测治疗的基于大脑的措施 结果。第三个目的是确定CHRNA 4 SNP是否调节伐尼克兰对细胞凋亡的影响。 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。 一项伐尼克兰对照试验，基线时进行神经影像学评估， 基线、2周、6周和12周以及6个月随访。拟议中的遗传变异研究， 预测对伐尼克兰的反应预期具有显著的临床意义。

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.