Brain Substrates of Extinction-Based Treatment for Nicotine Dependence

描述（由申请人提供）：一种基于灭绝的疗法（EBT），吸烟者在目标戒烟日期前的几周内抽去尼古丁（“denic”）香烟并佩戴尼古丁贴片，有望成为一种新的有效治疗尼古丁依赖的方法。这种EBT预处理（EBT- pre）打破了吸烟与尼古丁释放之间的偶然关系，从而促进了吸烟行为的消失，使吸烟者更容易戒烟。EBT-PRE比基于临床的ebt有潜在的优势，因为消除训练可以在各种各样的情况下进行（即在吸烟者通常吸烟的所有情况下）。因此，它可能不那么容易受到“更新效应”的影响，即在一种情况下的灭绝不会推广到其他情况。最近的EBT-PREs临床试验使用denics加尼古丁贴片，报告连续4周的戒断率在30%到50%之间。在最近的一项研究中，我们观察到EBT-PRE可以减弱大脑对杏仁核中吸烟相关信号的反应，杏仁核是奖励学习和消失的关键基础。本应用的首要目标是进一步阐明EBT-PRE的神经基础。100名（n=100）吸烟者将被随机分配到两个治疗组中的一个：一个基于消失的治疗组（EBT; n=50），参与者在戒烟日期前一个月戴着21毫克/天的尼古丁贴片吸烟；另一个尼古丁替代治疗组（NRT; n=50），参与者在戒烟日期前抽他们常用品牌的香烟。在戒烟日期之后，两组都将接受标准的尼古丁替代疗法。在此随机试验的基础上，将使用fMRI在基线[fMRI71]、预处理期第四周[fMRI72]和戒烟后24小时内[fMRI73]测量脑线索反应性（CR）。我们假设，与NRT相比，EBT将导致杏仁核对吸烟相关线索的反应性降低，并且基线时更大的脑CR（以及EBT对脑CR的更大衰减）将与更好的EBT结果相关。该项目建立在调查小组早期工作和专业知识的基础上，并高度响应RFA，寻求研究阐明“可能指导干预的灭绝机制”和“识别大脑机制……参与灭绝”。EBT-PRE代表了一种新的、潜在有效的、高度可传播的治疗尼古丁依赖的方法，阐明其潜在的神经机制将导致这种治疗的进一步完善。

DESCRIPTION (provided by applicant): An extinction-based therapy (EBT) in which smokers smoke denicotinized (`denic') cigarettes and wear a nicotine patch in the weeks leading up to a target quit date has shown promise as a novel and effective treatment for nicotine dependence. This EBT pretreatment (EBT-PRE) breaks the contingent relationship between smoking a cigarette and nicotine delivery, thus promoting extinction of smoking behavior and making it easier for the smoker to quit. EBT-PRE has a potential advantage over clinic- based EBTs in that extinction training can occur in a wide variety of contexts (i.e. in all of the contexts the smoker typically smokes). Therefore, it may not be as susceptible to the `renewal effect' in which extinction in one context does not generalize to others. Recent clinical trials of EBT-PREs using denics plus the nicotine patch have reported 4 week continuous abstinence rates in the 30 to 50% range. In a recent study, we observed EBT-PRE to attenuate brain reactivity to smoking-related cues in the amygdala-a critical substrate of reward learning and extinction. The overarching goal of the present application is to further elucidate the neural basis of EBT-PRE. One hundred (n=100) smokers will be randomly assigned to one of two treatment arms: an extinction-based therapy (EBT; n=50) arm in which participants will smoke denic cigarettes while wearing a 21 mg/d nicotine patch for one month prior to their quit date or a nicotine replacement therapy (NRT; n=50) arm in which participants will smoke their usual brand of cigarettes up to the quit date. Following the quit date, both groups will undergo standard nicotine replacement therapy. Overlaid on this randomized trial, brain cue-reactivity (CR) will be measured using fMRI at baseline [fMRI71], in the fourth week of the pretreatment period [fMRI72] and within 24 hrs of quitting smoking [fMRI73]. We hypothesize that EBT will result in decreased amygdalar reactivity to smoking-related cues compared to NRT and that greater brain CR at baseline (and greater attenuation of brain CR by EBT) will be associated with better EBT outcomes. This project builds upon the investigative team's earlier work and expertise and is highly responsive to the RFA which seeks research that elucidates the `mechanisms of extinction that might guide interventions' and `identifies brain mechanisms...involved in extinction'. EBT-PRE represents a novel, potentially effective and highly disseminable treatment for nicotine dependence and elucidating the neural mechanisms underlying it will lead to further refinement of this therapy. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. A new smoking cessation treatment seeks to break the relationship between smoking a cigarette and delivery of nicotine to the brain making it easier for smokers to quit. Clinical trials of this `extinction-based' therapy (EBT) suggest it is safe and potentially effective; however, little is known about how it changes brain function. The proposed research will lead to a better understanding of the neural basis of EBT which will lead to further refinement of this promising new treatment.