Characterizing a cue-vulnerable pharmaco-responsive endophenotype in smokers

表征吸烟者中线索脆弱的药物反应内表型

• 批准号: 8663849
• 负责人: TERESA R FRANKLIN
• 金额: $ 26.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663849
• 关键词: Adverse effects; Affect; Alleles; Amygdaloid structure; Behavioral; Behavioral Genetics; Behavioral Model; Brain; Candidate Disease Gene; Cessation of life; Characteristics; Cholinergic Receptors; Chronic; Cigarette; Clinical Trials; Cues; DNA; Data; Development; Exhibits; Foundations; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Genotype; Goals; Heterogeneity; Homozygote; Image; Individual; Insula of Reil; Knowledge; Label; Laboratory Study; Lateral; Lead; Link; Medial; Mediating; Medicine; Mental disorders; Methods; Minisatellite Repeats; Modeling; Monitor; National Institute of Drug Abuse; Nicotine Withdrawal; Perfusion; Pharmaceutical Preparations; Placebo Control; Placebos; Play; Process; Regimen; Relapse; Research Design; Rest; Rewards; Role; Sampling; Signal Transduction; Smoker; Smoking; Smoking Behavior; Subgroup; System; Testing; Time; Tobacco Dependence; Treatment outcome; Ventral Striatum; Withdrawal; Work; addiction; base; behavior measurement; craving; cue reactivity; design; dopamine transporter; drug craving; drug reward; endophenotype; innovation; meetings; novel; proband; relating to nervous system; response; smoking cessation; smoking relapse; success; tobacco abuse; treatment response; treatment strategy; varenicline

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.

描述（由申请人提供）：在美国，吸烟成瘾是可预防死亡的主要原因。两个主要因素导致继续吸烟和复吸：吸烟线索引起的渴望（SC）和尼古丁戒断引起的渴望（WD）。我们证明，SC激活奖励相关回路[（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。在饱腹的吸烟者（而不是WD）中获得的数据表明单独的SC可以影响响应。多巴胺转运蛋白SLC 6A 3（DAT）基因的变异深刻地影响了个体的反应：与10个VNTR纯合子的先证者相比，9个可变数目串联重复（VNTR）等位基因的携带者在SC暴露期间在奖励相关区域表现出增强的脑活动，可能确定了SC脆弱的内表型。这可能解释了对主要用于减少WD的戒烟药物的治疗反应的一些异质性，并进一步表明存在药物反应性内表型。伐尼克兰，这是两倍的其他药物的有效性，作用于烟碱胆碱能受体，以调节DA系统。我们目前的数据表明，伐尼克兰减少主观的渴望和钝化的SC在'奖励激活' mOFC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。这些数据意味着伐尼克兰的更大疗效可能是相互作用的函数。因此，varenicline是表征SC脆弱性的大脑和遗传基础的理想探针。本申请的总体目标是表征SC易感的药物反应性内表型。为了实现这一目标，我们将1）确认并扩展9个VNTR携带者在SC暴露期间具有更大的脑和行为反应的发现，鉴定SC-脆弱的内表型，2）扩展初步的脑和行为发现以表征伐尼克林-反应性内表型，和3）检查DAT方差与伐尼克兰诱导的脑和行为反应之间的相互作用，以确定SC-易感的药物，反应性内表型试验设计：使用创新的大脑/行为模型，允许直接比较药理学操作随时间的影响，提供药物作用的潜在机制的知识，将在3周药物治疗方案之前和之后采集数据。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。成像后，将使用新的自然方法监测吸烟行为。将分析DNA样本中DA调节基因的等位基因变异。重要性：这些研究将明确地将SC诱导的边缘系统激活与吸烟行为联系起来;确定有效药物治疗的脑机制特征，从而提供一个模型来测试新分子的预测有效性;并描述吸烟者中伐尼克林反应性内表型，这可能导致个性化治疗策略和更大的戒烟成功。