Clinical Relevance of Stress Neuroadaptation in Tobacco Dependence

描述（由申请人提供）：动物模型神经科学研究表明，应激反应中的神经适应是多种药物（包括尼古丁）成瘾病因学的关键机制。由于长期给药，大脑压力系统中的反复稳态调整最终导致参与情绪反应及其调节的结构中的持续补偿性适应。在吸烟者中，当尼古丁被剥夺时，这些压力神经适应导致失调的负面影响，并为进一步吸烟提供强大的动机压力，表现为冲动和戒烟失败的风险增加。 动物模型提供了大量的证据来支持成瘾中的这种应激神经适应性论点，然而，检查尼古丁剥夺和非剥夺吸烟者（相对于非吸烟者）的应激反应的程序性实验室研究是必要的，以证实我们对动物模型的应激神经适应性的理解转化为吸烟者的成瘾病因。负面影响是人类药物戒断综合征的核心动机因素，包括尼古丁在内的添加剂药物。不幸的是，我们对人类这些动机关键的情感过程的了解，大部分都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没有跟上情感科学在概念、方法和测量方面的快速进步。此外，补充方法（例如，实验室任务操作，临床治疗干预）和测量方法（例如，心理生理学、生态瞬时评估）很少结合。 本申请中的研究利用了最近对动物和人类的研究，这些研究已经合成了精确的实验室压力操作与惊吓反射增强的敏感心理生理测量，以将对压力的情感反应解析为其组成成分。特别是，在不确定（与确定） 威胁有望成为慢性尼古丁或其他药物使用后应激神经适应的生物标志物。我们建议在实验室通过惊吓增强不确定的威胁在两个验证的线索威胁任务尼古丁剥夺和非剥夺吸烟者和非吸烟者之间的压力神经适应。吸烟者随后将在戒烟治疗期间被分配至复方NRT或安慰剂组，并将通过生态瞬时评估程序报告偶发性压力源、负面影响、吸烟冲动和吸烟。将在退出后2周评估治疗结局。 本研究的主要目标是确定慢性吸烟导致的应激神经适应的病因学相关的心理生理生物标志物。我们评估了这种压力神经适应对吸烟者在戒烟治疗期间的真实世界的影响，敦促和吸烟。我们还评估了NRT是否可以通过其对戒断的影响来减弱这种应激神经适应对戒烟结果的影响。

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.