Clinical Relevance of Stress Neuroadaptation in Tobacco Dependence

描述（由申请人提供）：动物模型的神经科学研究表明，应激反应中的神经适应是包括尼古丁在内的多种药物成瘾病因学的关键机制。由于长期服药，大脑应激系统中的反复稳态调整最终导致持续的代偿性适应，这些适应涉及情绪反应及其调节的结构。在吸烟者中，当尼古丁被剥夺时，这些压力神经适应会导致不受控制的负面影响，并为进一步吸烟提供强大的动机压力，表现为强烈的戒烟冲动和戒烟失败的风险增加。动物模型已经提供了大量证据来支持这种成瘾中的应激神经适应理论。然而，有必要进行程序化的实验室研究，检查尼古丁剥夺和非剥夺吸烟者（相对于非吸烟者）的应激反应，以证实我们对动物模型的应激神经适应的理解转化为吸烟者的成瘾病因学。负面影响是人类药物戒断综合征的核心动机因素，包括尼古丁。不幸的是，我们对人类这些动机关键情感过程的了解大多是基于孤立收集的狭窄范围的测量。在过去的十年里，对消极情绪的特征和神经生物学基础的研究并没有跟上情感科学在概念、方法和测量方面的快速发展。此外，互补的方法（如实验室任务操作、临床治疗干预）和测量方法（如心理生理学、生态瞬时评估）很少结合起来。本应用程序的研究利用了最近对动物和人类的研究，这些研究综合了精确的压力实验室操作和惊吓反射增强的敏感心理生理测量，将对压力的情感反应解析为其组成部分。特别是，在不确定（相对于确定）的情况下，惊吓增强

DESCRIPTION (provided by applicant): Neuroscience research with animal models implicates neuroadaptation in the stress response as a critical mechanism in the etiology of addiction across multiple classes of drugs including nicotine. Repeated homeostatic adjustments in the brain's stress systems due to chronic drug administration eventually lead to persistent compensatory adaptations in the structures involved in emotional response and its regulation. Among smokers, these stress neuroadaptations result in deregulated negative affect when nicotine-deprived and provide the strong motivational press for further smoking that manifests as urge and increased risk for smoking cessation failure. Animal models have provided substantial evidence to support this stress neuroadaptation thesis in addiction However, programmatic laboratory research that examines the stress response in nicotine deprived and non- deprived smokers (relative to non-smokers) is necessary to confirm that our understanding of stress neuroadaptations from animal models translate to addiction etiology in smokers. Negative affect is the core motivational element of the human drug withdrawal syndrome across additive drugs including nicotine. Unfortunately, much of what we know about these motivationally critical affective processes in humans is based on a narrow range of measures collected in isolation. The examination of the characteristics and neurobiological substrates of negative affect has not kept pace with the rapid conceptual, methodological, and measurement advances in the affective sciences over the past decade. Moreover, complementary methods (e.g., laboratory task manipulations, clinical treatment interventions) and measurement approaches (e.g., psychophysiology, ecological momentary assessment) are rarely combined. The research in this application capitalizes on recent research with both animals and humans that has synthesized precise laboratory manipulations of stress with sensitive psycho physiological measurement of startle reflex potentiating to parse the affective response to stress into its constituent components. In particular, startle potentiating during uncertain (vs. certain) threats holds promise as a biomarker of stress neuroadaptation following chronic nicotine or other drug use. We propose to measure stress neuroadaptation in the laboratory via startle potentiating during uncertain threat in two validated cued threat tasks among nicotine deprived and non-deprived smokers and non-smokers. Smokers will be subsequently assigned to combo NRT or placebo during smoking cessation treatment and will report on episodic stressors, negative effect, smoking urge, and smoking via ecological momentary assessment procedures. Treatment outcome will be assessed at 2 weeks post-quit. The broad goals of this research are to identify etiologically relevant psycho physiological biomarkers of stress neuroadaptation that results from chronic smoking. We evaluate the impact of this stress neuroadaptation on smokers' real-world affect, urge and smoking during smoking cessation treatment. We also evaluate if NRT can attenuate the influence of this stress neuroadaptation on smoking cessation outcomes via its effects on withdrawal. PUBLIC HEALTH RELEVANCE: This research will translate neuroscience findings from animal models to clinical research on tobacco dependence in humans. Its goal is to identify precise biomarkers of etiologically relevant stress neuroadaptations that result from chronic smoking. This research can aid targeted pharmacological and psychological treatment development and identify processes that are obstacles to cessation of smoking and/or increase risk for relapse among smokers.