Stress Response and Opioid Dysfunction in Nicotine Dependence

描述（由申请人提供）：我们迄今为止的研究表明，吸烟者对多种应激过程表现出增强的基底下丘脑-垂体-肾上腺皮质（HPA）活性和减弱的皮质醇反应。我们特别重要的发现是，这种应激反应的改变预示着吸烟的早期复发。众所周知，内源性阿片系统在HPA调节中起着至关重要的作用，这两个系统都参与调节情绪和加强药物使用的作用。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的破坏尚不清楚，这是拟议研究的重点。关于阿片阻断对下丘脑应激反应影响的初步研究结果表明，阿片张力降低可能是一个潜在的重要机制。这些阿片类hpa改变在多大程度上被戒烟所改变，以及它们在多大程度上加剧了与戒烟相关的症状，将由本研究来阐明。我们还证明了复发预测因子的性别差异。拟议的研究将检查和澄清女性和男性依赖吸烟者在阿片类药物阻断挑战和应激反应期间激素反应模式的性别差异。综上所述，迄今为止的研究结果以及对应激对吸烟影响的重要途径的潜在发现表明了描述阿片类药物- hpa相互作用的重要性。在戒烟者和应激反应中确认内源性阿片张力失调，将为进一步研究开发尼古丁依赖、压力相关渴望和复发的生物行为标志物奠定基础。

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.