Characterizing a cue-vulnerable pharmaco-responsive endophenotype in smokers

描述(申请人提供)：在美国，吸烟成瘾是可预防的死亡的主要原因。两个主要因素导致持续吸烟和复发：由吸烟线索(SC)引起的渴望和由尼古丁戒断(WD)引起的渴望。我们证明了SCs激活奖赏相关回路[(腹侧纹状体、内侧眶前皮质(MOFC)])，并将大脑的反应与随后的吸烟行为联系起来。数据是在饱受的吸烟者(而不是WD)中获得的，表明SCs本身就可以影响反应。多巴胺转运体SLC6A3(DAT)基因的变异深刻地影响了个体的反应：在SC暴露期间，携带9个可变数目串联重复(VNTR)等位基因的人在奖赏相关区域的脑活动比携带10VNTR纯合子的先证者更强，这可能表明SC易受攻击。这可能解释了对主要作用于减少WD的戒烟药物治疗反应的一些异质性，并进一步表明存在药物反应内表型。作用于烟碱型胆碱能受体以调节DA系统的Varenicline的效力是其他药物的两倍。我们提供的数据表明，在“奖赏激活”的mOFC中，varenicline降低了主观渴望，并钝化了对SC的反应。此外，效果与休息时大脑中“奖赏评估”侧脑OFC的活动呈负相关。这些数据表明，varenicline的更大疗效可能是相互作用的函数。因此，varenicline是表征SC易损性的大脑和遗传基础的理想探针。这项应用的总体目标是鉴定SC脆弱的药物反应内表型。为了实现这一目标，我们将1)确认和扩大这一发现，即9名VNTR携带者在SC暴露期间有更大的大脑和行为反应，确定SC脆弱的内表型，2)扩大初步的脑和行为发现，以表征Varenicline反应的内表型，以及3)研究DAT变异和Varenicline诱导的脑和行为反应之间的相互作用，以确定SC易受药物反应的内表型。研究设计：使用一种创新的大脑/行为模型，允许随着时间的推移直接比较药物操作的效果，提供关于药物效果的潜在机制的知识，数据将在3周用药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暴露于SC期间进行成像。在成像过程之后，吸烟行为将使用新的自然主义方法进行监测。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；识别有效药物的大脑机制，从而提供一个模型来测试新分子的预测有效性；并描述吸烟者对varenicline反应的内表型，这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.