Characterizing a cue-vulnerable pharmaco-responsive endophenotype in smokers

描述（由申请人提供）：烟瘾是美国可预防性死亡的主要原因。两个主要因素导致持续吸烟和复发：吸烟线索引起的渴望（SCs）和尼古丁戒断引起的渴望（WD）。我们证明了SCs激活了与奖励相关的回路（腹侧纹状体，内侧眶额皮质（mOFC）），并将大脑的反应与随后的吸烟行为联系起来。在健康吸烟者（非WD）中获得的数据表明，SCs单独可以影响应答。多巴胺转运体SLC6A3 （DAT）基因的变异深刻影响个体反应：与10可变数串联重复（VNTR）等位基因的先证者纯合子相比，在SC暴露期间，9可变数串联重复（VNTR）等位基因的携带者在奖励相关区域表现出增强的大脑活动，可能识别SC易感的内表型。这可以解释戒烟药物治疗反应的一些异质性，戒烟药物主要是为了减少WD，进一步表明存在药物反应性内表型。伐尼克兰的效果是其他药物的两倍，它作用于烟碱胆碱能受体来调节DA系统。我们提供的数据表明，伐尼克兰减少了主观渴望，并减弱了“奖励激活”的mOFC中对SCs的反应。此外，效果与休息时大脑中“奖励评估”侧OFC的活动呈负相关。这些数据表明，伐尼克兰的更大疗效可能是相互作用的结果。因此，伐尼克兰是表征大脑和SC易感性遗传基础的理想探针。表征sc易损的药物反应性内表型是本应用的总体目标。为了实现这一目标，我们将1)证实并扩展9名VNTR携带者在SC暴露期间有更大的大脑和行为反应的发现，以确定SC易损的内表型；2)扩展初步的大脑和行为发现，以表征伐尼克兰反应性的内表型；3)检查数据差异与伐尼克兰诱导的大脑和行为反应之间的相互作用，以确定SC易损的药物反应性内表型。研究设计：使用一种创新的大脑/行为模型，可以直接比较药物操作随时间的影响，提供药物作用的潜在机制的知识，数据将在3周药物治疗方案之前和之后获得。在每个时间点，吸烟者将在休息条件下和SC暴露期间进行成像。在影像学检查之后，将使用新颖的自然方法监测吸烟行为。DNA样本将被分析DA调节基因的等位基因变异。意义：这些研究将明确地将sc诱导的边缘激活与吸烟行为联系起来；确定有效药物的脑机制特征，从而为测试新分子的预测有效性提供模型；并描述吸烟者的伐尼克林反应性内表型，这将有可能导致个性化的治疗策略和更大的戒烟成功。

DESCRIPTION (provided by applicant): Cigarette addiction is leading cause of preventable death in the USA. Two major factors contribute to continued smoking and relapse: craving elicited by smoking cues (SCs), and craving elicited by nicotine withdrawal (WD). We demonstrated that SCs activate reward-related circuitry [(ventral striatum, medial orbitofrontal cortex (mOFC)], and linked the brain's response to subsequent smoking behavior. Data were acquired in sated smokers (not in WD) demonstrating that SCs alone can affect responses. Variance in the dopamine transporter SLC6A3 (DAT) gene profoundly affected individual responses: Carriers of a 9 variable number tandem repeat (VNTR) allele exhibited enhanced brain activity in reward-related regions during SC exposure compared to probands homozygous for the 10 VNTR, possibly identifying a SC-vulnerable endophenotype. This may explain some of the heterogeneity in treatment response to smoking cessation medications that act primarily to reduce WD, and further, suggests the existence of pharmaco-responsive endophenotypes. Varenicline, which is twice as effective as other agents, acts on nicotinic cholinergic receptors to modulate the DA system. We present data that varenicline reduces subjective craving and blunts responses to SCs in the 'reward activated' mOFC. Further, effects were inversely correlated with activity of the 'reward evaluating' lateral OFC in the brain at rest. These data imply that the greater efficacy of varenicline may be a function of the reciprocal actions. As such, varenicline is an ideal probe for characterizing the brain and genetic underpinnings of SC vulnerability. Characterization of a SC-vulnerable pharmaco-responsive endophenotype is the overall goal of this application. Towards this goal, we will 1) confirm and extend the finding that 9 VNTR carriers have greater brain and behavioral responses during SC exposure, identifying a SC-vulnerable endophenotype, 2) expand preliminary brain and behavioral findings to characterize a varenicline-responsive endophenotype, and 3) examine the interaction between DAT variance and varenicline- induced brain and behavioral responses to identify a SC-vulnerable pharmaco-responsive endophenotype. Study design: Using an innovative brain/behavioral model that allows for direct comparisons of the effects of pharmacological manipulations over time, providing knowledge of the underlying mechanism of medication effects, data will be acquired prior to and following a 3 week medication regimen. At each time point smokers will be imaged under conditions of rest and during SC exposure. Following imaging sessions, smoking behavior will be monitored using novel naturalistic methods. DNA samples will be analyzed for allelic variance in DA regulating genes. Significance: These studies will definitively link SC-induced limbic activation and smoking behavior; identify brain mechanisms characteristic of effective medication, thus, providing a model to test the predictive validity of novel molecules; and characterize a varenicline-responsive endophenotype in smokers that will potentially lead to personalized treatment strategies and greater smoking cessation success.