Pharmacogenetics, Emotional Reactivity & Smoking(RMI)

描述（由申请人提供）：戒烟的最新进展主要集中在使用抗抑郁药治疗尼古丁依赖（即安非他酮和去甲替林）。虽然这些治疗方法的有效性已经在以前的研究中得到证实，但我们对它们的作用机制知之甚少，尤其是对负面情绪的症状，这些症状既是复发的有力预测因素，也是这些药物的主要目标。通过提高我们对戒烟期间情绪调节的心理生物学和遗传机制的理解，以及这些机制与治疗之间的相互作用，这些药物治疗和其他药物治疗的影响可能会得到加强。该项目的具体目的是评估这些药物对戒烟期间情绪反应变化的影响，并确定这些影响是否受到基因型的调节。我们还将确定情绪反应是否预测复发时间。惊吓反射（眨眼）是研究药物、遗传因素和其他心理生物学机制对情绪处理影响的新兴技术。惊吓反射是一种定向反应，跟随一个意想不到的听觉刺激（惊吓探针）。消极的情绪线索（不愉快的图片）激活防御性神经调节通路，增加眨眼反应幅度（眼肌肌电图），积极的线索（愉快的图片）抑制反应，激活食欲或接近行为，在防御性激活中，积极的线索抑制反应（食欲激活）。我们之前的研究表明，这种反应在戒烟前后受到DRD2基因型的调节。在这项研究中，多达354名吸烟者将被随机分配接受安非他酮、去甲替林或安慰剂。参与者将在基线（戒烟前）和戒烟后2、5和28天完成惊吓评估，包括声音刺激（惊吓探针）的呈现，紧接着是积极、消极或中性的情绪暗示或吸烟相关刺激。我们假设，与安慰剂相比，接受抗抑郁药治疗的所有吸烟者在戒烟期间的情绪反应都会明显减少。还有一种假设是，携带DRD2 A1等位基因并使用安非他酮的人的情绪反应要低于使用去甲替林或安慰剂的A1吸烟者。纯合子A2s预期对两种药物的反应相似，但观察到安慰剂的情绪反应水平更高。我们还将描述神经递质功能的其他潜在标志物（DRD4， DAT， SERT， NET）在基线情绪反应和对药物治疗的反应方面与对照组的差异。我们希望通过这种机制更全面地了解戒烟药物治疗如何影响戒烟期间的情绪反应（尼古丁戒断），以及遗传学在赋予一种治疗相对于另一种治疗优势方面可能发挥的作用。最终，这些知识可以应用于开发更有效的戒烟治疗，特别是在药物遗传学领域。

DESCRIPTION (provided by applicant): Recent advances in smoking cessation have focused on the use of antidepressants for the treatment of nicotine dependence (i.e., bupropion and nortriptyline). While the efficacy of these treatments has been established in previous studies, we know little about how they work, particularly on symptoms of negative affect, which are both a strong predictor of relapse and a primary target of these drugs. The impact of these and other pharmacological treatments may be enhanced by improving our understanding of the psychobiological and genetic mechanisms associated with the modulation of mood during cessation and the interaction between these mechanisms and treatment. The specific aims of this project are to assess the effects of these drugs on changes in emotional reactivity during cessation, and to determine if these effects are moderated by genotype. We will also determine whether emotional reactivity predicts time to relapse. The startle reflex (eye blink) is an emerging technology for studying the impact of drugs, genetic factors and other psychobiological mechanisms on emotional processing. The startle reflex is an orienting response that follows an unexpected auditory stimulus (startle probe). Negative emotional cues (unpleasant pictures) activate defensive neuroregulatory pathways and increase blink response magnitude (eye muscle EMG), while positive cues (pleasant pictures) inhibit the response, activating appetitive or approach behavior, in defensive activation, while positive cues inhibit the response (appetitive activation). Our previous studies suggest that this response is modulated before and after quitting by the DRD2 genotype. In this study, up to 354 smokers will be randomly assigned to receive bupropion, nortriptyline or placebo. Participants will complete a startle assessment at baseline (pre-quit) and at 2, 5 and 28 days post-quit, consisting of the presentation of an acoustic stimulus (startle probe), immediately preceded by positive, negative or neutral emotional cues or smoking related stimuli. We hypothesize that the emotional reactivity of all smokers during cessation will be significantly less for those treated with either antidepressant in comparison to placebo. It is also hypothesized that emotional reactivity will be lower for those carrying the DRD2 A1 allele and using bupropion versus A1 smokers using either nortriptyline or placebo. Homozygous A2s are expected to respond similarly to both drugs with higher levels of emotional reactivity being observed for placebo. We will also characterize other potential markers for neurotransmitter function (DRD4, DAT, SERT, NET) in terms of differences in both baseline emotional reactivity, and response to pharmacotherapy vs: the control. We hope to understand more fully how pharmacotherapies for smoking cessation affect emotional reactivity during cessation (nicotine withdrawal) and what role genetics may play in conferring an advantage to one treatment versus another, through this mechanism. Ultimately this knowledge may be applied to the development of more effective smoking cessation treatments, especially in the area of pharmacogenetics.