Targeting reward dysfunction as a mechanism to improve smoking cessation

 描述（由申请人提供）：吸烟仍然是发达国家死亡和残疾的主要原因。许多想戒烟的人都无法做到。尽管在确定尼古丁依赖的神经行为机制方面取得了重大进展，但仍迫切需要将这些发现转化为有针对性的有效干预措施，并了解成功干预措施发挥作用的机制。理论模型和越来越多的实证文献表明，成瘾性疾病，包括烟草依赖，其特征是中脑边缘对吸烟奖励和相关线索的超敏反应和对非吸烟奖励的低敏反应，特别是在戒烟尝试的早期阶段发生的戒断过程中。这种失调的奖励处理可能代表了抑郁症状个体的一种特殊脆弱性，可能导致复发，并提出了一个有希望的干预目标。本申请中提出的研究的总体目标是开发和评估一种新的干预措施，该干预措施通过以下两种方式直接靶向这种奖励处理失衡：a）通过用极低尼古丁香烟（VLNC）预处理减少吸烟强化，和B）通过行为激活（BA）增加来自其他非药物奖励的强化。该研究的目的如下：1）比较BA + VLNC与仅VLNC对轻度抑郁症状吸烟者的中脑边缘反应性和对吸烟和金钱奖励的主观敏感性的影响; 2）收集BA + VLNC联合戒烟效果的初步数据;探讨治疗前后脑功能对吸烟结局的中介和调节作用。这项拟议的研究建立在主要研究者Maggie Sweitzer博士以前的经验基础上，并与她的总体职业发展目标密切相关，即成为一名独立的研究者，在开发和评估戒烟的机械信息治疗方面具有专业知识。Sweitzer博士是杜克大学医学中心的临床助理，在吸烟的行为药理学和功能性神经成像方面具有专长。该应用程序的主要培训目标是获得以下方面的技能：a）先进的神经科学和神经成像方法; B）治疗开发和评估; c）进行临床试验; d）道德和负责任的研究行为。拟议的研究和培训计划的结果将促进Sweitzer博士作为独立研究者的发展，并为未来更大规模的疗效研究提供初步数据。

 DESCRIPTION (provided by applicant): Tobacco smoking remains a leading cause of death and disability in the developed world. Many who wish to quit smoking are unable to do so. Although substantial advances have been made to identify neurobehavioral mechanisms underlying nicotine dependence, there is a great need to translate these findings into targeted, efficacious interventions, and to understand the mechanisms by which successful interventions exert their effects. Theoretical models and a growing empirical literature suggest that addictive disorders, including tobacco dependence, are characterized by mesolimbic hypersensitivity to smoking reward and related cues and hyposensitivity to nonsmoking rewards, particularly during the withdrawal that occurs during the early stages of a quit attempt. This dysregulated reward processing may represent a particular vulnerability for individuals with depressive symptoms that is likely to contribute to relapse and presents a promising target for intervention. The overarching goal of the research proposed in this application is to develop and evaluate a novel intervention that directly targets this reward processing imbalance by both a) decreasing smoking reinforcement through pretreatment with very low nicotine cigarettes (VLNC's) and b) increasing reinforcement from other non-drug rewards through behavioral activation (BA). The proposed research study has the following aims: 1) To examine the effects of BA + VLNC compared with VLNC only on mesolimbic reactivity and subjective sensitivity to smoking and monetary rewards among smokers with mild depressive symptoms; 2) To gather preliminary data on the effects of combined BA + VLNC on smoking cessation outcomes; and 3) To explore mediating and moderating effects of pre-and post-treatment brain function on smoking outcomes. The proposed research builds upon the Principle Investigator, Dr. Maggie Sweitzer's, previous experience and is closely aligned with her overarching career development goal of becoming an independent investigator with expertise in the development and evaluation of mechanistically-informed treatments for smoking cessation. Dr. Sweitzer is a clinical associate at Duke University Medical Center with expertise in behavioral pharmacology of smoking and functional neuroimaging. The primary training goals of this application are to gain skills in a) advanced neuroscience and neuroimaging methods; b) treatment development and evaluation; c) conducting clinical trials; and d) ethical and responsible conduct of research. The results of the proposed research and training plans will facilitate Dr. Sweitzer's development as an independent investigator and provide preliminary data for a future larger scale efficacy study.