Pharmacogenetics, Emotional Reactivity & Smoking

描述(由申请人提供)：戒烟方面的最新进展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)。虽然这些治疗的有效性已经在之前的研究中得到了证实，但我们对它们是如何起作用的知之甚少，特别是对负面情绪的症状，这既是复发的有力预测因素，也是这些药物的主要靶点。通过提高我们对戒烟过程中情绪调节的心理生物学和遗传学机制的理解，以及这些机制和治疗之间的相互作用，这些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在戒烟过程中对情绪反应性变化的影响，并确定这些影响是否受到基因型的影响。我们还将确定情绪反应是否预示着复发的时间。惊吓反射(眨眼)是一项新兴技术，用于研究药物、遗传因素和其他心理生物机制对情绪处理的影响。惊吓反射是一种跟随意外听觉刺激(惊吓探头)的定向反应。消极的情绪暗示(不愉快的图片)激活防御性神经调节通路并增加眨眼反应幅度(眼肌肌电)，而积极的情绪暗示(愉快的图片)在防御激活时抑制反应，激活食欲或接近行为，而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都受到DRD2基因的调节。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)以及戒烟后2、5和28天完成惊吓评估，包括展示声学刺激(惊吓探头)，紧接着是积极、负面或中性的情绪暗示或与吸烟有关的刺激。我们假设，与安慰剂相比，接受任何一种抗抑郁药物治疗的吸烟者在戒烟期间的情绪反应明显较少。还假设携带DRD2 A1等位基因并使用安非他酮的吸烟者的情绪反应性将低于使用去甲替林或安慰剂的A1吸烟者。预计纯合子A2对这两种药物的反应相似，安慰剂的情绪反应水平更高。我们还将根据基线情绪反应和对药物治疗的反应与对照组的差异来表征神经递质功能的其他潜在标记物(DRD4、DAT、SERT、NET)。我们希望更充分地了解戒烟药物疗法如何影响戒烟期间的情绪反应(尼古丁戒断)，以及通过这种机制，遗传学在赋予一种疗法相对于另一种疗法的优势方面可能发挥什么作用。最终，这些知识可能被应用于开发更有效的戒烟治疗方法，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.