Stress Response and Opioid Dysfunction in Nicotine Dependence

描述(由申请人提供)：到目前为止，我们的研究表明，吸烟者表现出基础下丘脑-垂体-肾上腺皮质(HPA)活性增强，皮质醇对多种应激程序的反应减弱。我们特别重要的发现是，这种改变的压力反应预示着早期吸烟复发。众所周知，内源性阿片系统在HPA调节中起关键作用，这两个系统都参与调节情绪和加强药物使用的效果。吸烟者HPA反应的改变在多大程度上是由于内源性阿片类药物调节中断所致，目前尚不清楚，这是拟议研究的重点。关于阿片类药物阻断对HPA应激反应影响的初步研究结果表明，阿片类药物张力降低可能是一个潜在的重要机制。这项研究将阐明戒烟在多大程度上改变了这些阿片-HPA的变化，以及它们在多大程度上加剧了与戒烟相关的症状。我们还展示了复发预测因素的性别差异。这项拟议的研究将检查和澄清在阿片类药物阻断挑战期间以及在对依赖的女性和男性吸烟者的压力反应中，激素反应模式的性别差异。综上所述，到目前为止的发现和可能发现的吸烟压力效应的重要途径表明了描绘阿片类药物-HPA相互作用的重要性。证实戒烟者的内源性阿片张力失调并对压力做出反应，将为进一步研究开发尼古丁依赖、应激相关渴望和复发的生物行为标记物奠定基础。 公共卫生相关性：烟草成瘾/依赖是癌症和心血管疾病的主要可预防原因。压力被广泛认为是持续吸烟的原因，也是那些试图实现长期戒烟的人复发的原因。这项拟议的研究扩展了我们的计划，以确定吸烟压力影响的生物行为机制和决定因素。这将为确定复发易感性标记的研究奠定基础。反过来，这将为预测和制定有针对性的干预措施提供独特的机会。

DESCRIPTION (provided by applicant): Our research to date has demonstrated that cigarette smokers exhibit enhanced basal hypothalamic-pituitary-adrenocortical (HPA) activity and attenuated cortisol responses to multiple stress procedures. Our particularly important finding has been that this altered stress response predicts early smoking relapse. It is well-established that the endogenous opioid system plays a critical role in HPA regulation and that both systems are involved in regulating mood and reinforcing effects of drug use. The extent to which altered HPA response in smokers is due to disrupted endogenous opioid regulation is unknown and is the focus of the proposed research. Preliminary findings on the effects of opioid blockade on HPA stress response indicate that diminished opioid tone may be one potentially important mechanism. The extent to which these opioid-HPA alterations are modified by smoking abstinence and the extent to which they exacerbate symptoms associated with abstinence will be elucidated by this research. We have also demonstrated sex differences with respect to relapse predictors. The proposed research will examine and clarify sex differences in hormonal response patterns during an opioid blockade challenge and in response to stress in dependent female and male smokers. In combination, the findings to date and the potential discovery of an important pathway for stress effects on smoking point to the importance of delineating the opioid-HPA interactions. Confirmation of dysregulated endogenous opioid tone in abstinent smokers and in response to stress will set the stage for refined investigations to develop biobehavioral markers of nicotine dependence, stress-related craving, and relapse. PUBLIC HEALTH RELEVANCE: Tobacco addiction/dependence is the leading preventable cause of cancer and cardiovascular diseases. Stress is widely cited as a reason for continued smoking and for relapse in those attempting to achieve long term abstinence. The proposed research extends our program to identify biobehavioral mechanisms and determinants of stress effects on smoking. This will set the stage for research to determine relapse vulnerability markers. In turn, this will provide unique opportunities for prediction and development of targeted interventions.