Brain Substrates of Extinction-Based Treatment for Nicotine Dependence

描述(由申请人提供)：一种基于戒烟的疗法(EBT)，吸烟者在目标戒烟日期前的几周内吸食去尼古丁香烟并佩戴尼古丁贴片，已显示出作为尼古丁依赖的一种新的有效治疗方法的前景。这种EBT预处理(EBT-PRE)打破了吸烟和尼古丁释放之间的或有关系，从而促进了吸烟行为的消退，使吸烟者更容易戒烟。与以临床为基础的EBTS相比，EBT-PRE具有潜在的优势，因为消除训练可以在各种情况下进行(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。最近使用Denics加尼古丁贴片的EBT-PRES临床试验报告称，4周的连续戒断率在30%到50%之间。在最近的一项研究中，我们观察到EBT-PRE可以减弱杏仁核对吸烟相关线索的大脑反应--杏仁核是奖赏学习和灭绝的关键底物。本申请的主要目的是进一步阐明EBT-PRE的神经基础。100名吸烟者将被随机分配到两个治疗组中的一个：基于戒烟的治疗(EBT；n=50)组，参与者在戒烟前一个月内每天佩戴21 mg/d尼古丁贴片吸烟；或者尼古丁替代疗法(NRT；n=50)，参与者将在戒烟日期之前吸他们通常品牌的香烟。戒烟日期后，两组都将接受标准的尼古丁替代疗法。在这项随机试验的基础上，将在基线[fMRI71]、预备期的第四周[fMRI72]和戒烟后24小时内[fMRI73]使用fMRI测量大脑线索反应性(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，基线时更大的大脑CR(以及EBT对大脑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的工作和专业知识的基础上，并高度响应RFA，后者寻求进行研究，阐明“可能指导干预的灭绝机制”，并“确定……参与灭绝的大脑机制”。EBT-PRE代表了一种新的、潜在有效和高度可传播的尼古丁依赖治疗方法，阐明其背后的神经机制将导致这种治疗方法的进一步完善。 与公共健康相关：在美国，吸烟是主要的可预防的死亡和残疾原因。一种新的戒烟疗法旨在打破吸烟和尼古丁向大脑传递之间的关系，使吸烟者更容易戒烟。这种基于消退的疗法(EBT)的临床试验表明，它是安全和潜在有效的；然而，人们对它如何改变大脑功能知之甚少。这项拟议的研究将使人们更好地了解EBT的神经基础，从而进一步完善这一有前途的新疗法。

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.