Regulation of Craving Under Stress: Novel Model and Neural Mechanisms

 描述（由申请人提供）：渴望和调节它的能力越来越多地被认为在维持成瘾（包括尼古丁依赖）和预防复发方面具有关键作用。为了研究这些重要的过程，我们开发了渴望调节（ROC）任务1 -5。在这项任务中，尼古丁依赖的吸烟者暴露于吸烟相关的刺激。在渴望条件下，他们被指示去思考与吸烟相关的愉快感觉，这导致了对香烟的渴望。然后，在调节条件下，他们被指示使用认知策略来调节他们对香烟的渴望 (e.g.,“想想吸烟的负面影响”）1。我们使用ROC任务和功能性磁共振成像（fMRI）来证明自我报告的渴望在调节条件下显着减少，这取决于与认知控制相关的前额叶皮层区域的招聘，如背外侧前额叶皮层2，6。我们还表明，这些大脑区域的招聘，反过来，调节活动皮层下区域的基础渴望，如腹侧纹状体2，3，7。压力是导致吸毒，特别是吸烟的另一个关键因素。一个主要的假设是，压力通过增强渴望和与渴望相关的大脑区域（包括腹侧纹状体）的神经活动而导致吸烟和复吸9-11。然而，最近的研究表明，压力也会损害前额叶功能12。因此，压力可能通过两种不同的途径导致吸毒：（1）增强渴望和渴望相关区域的神经活动（如其他成瘾所示），以及（2）通过减少前额功能来损害渴望的调节。为了测试我们的新模型并评估这些替代假设，我们将在90分钟的fMRI会议期间对84名尼古丁依赖吸烟者和84名匹配的健康对照者进行ROC任务。我们将使用电击的威胁，这是已知的诱导急性应激对一半的试验。然后，我们将比较（a）自我报告和（B）渴望和调节条件下的神经活动，采用2x2 x2析因设计：2个ROC条件（渴望与调节）x 2个压力条件（休克威胁与免于休克）x 2个刺激类型（香烟与食欲食物对照）。为了确定我们研究结果的临床相关性，我们将评估每种效应（渴望压力与调节压力）对吸烟严重程度的贡献。最后，我们将初步探讨压力、渴望和渴望调节方面的性别和个体差异，因为有证据表明它们可能会减轻压力和渴望的影响，并对戒烟产生影响。该项目有望促进我们对压力，渴望和渴望的调节的神经生物学理解，以及它们对吸烟的相互作用和贡献。反过来，这将提供一个新的理论框架来理解现有的压力和物质使用数据，并调整当前的治疗方法，以专门解决渴望压力及其调节的影响。

 DESCRIPTION (provided by applicant): Craving and the ability to regulate it are increasingly recognized for having key roles in the maintenance of addictions including nicotine dependence, and the prevention of relapse. To investigate these important processes, we developed the Regulation of Craving (ROC) task1-5. In this task, nicotine- dependent smokers are exposed to smoking-related stimuli. In the craving condition, they are instructed to think of the pleasant feelings associated with smoking, which results in cigarette craving. Then, in the regulation condition, they are instructed to use a cognitive strategy to regulate their craving for cigarettes (e.g., `think of the negative consequences associated with smoking')1. We used the ROC task and functional magnetic resonance imaging (fMRI) to demonstrate that self-reported craving is significantly reduced during the regulation condition, and that this depends on recruitment of regions in prefrontal cortex associated with cognitive control, such as dorsolateral prefrontal cortex2, 6. We have also shown that recruitment of these brain regions, in turn, modulates activity in subcortical regions that underlie craving, such as the ventral striatum2, 3, 7. Stress s another key factor contributing to drug use in general and smoking in particular8. A leading hypothesis is that stress contributes to smoking and relapse by potentiating craving and neural activity in brain regions associated with craving (including ventral striatum)9-11. However, recent research suggests that stress can also impair prefrontal function12. Thus, it is possible that stress may lead to drug use via two distinct routes: by (1) potentiating craving and neural activity in craving-related regions (as shown with other addictions), and also (2) compromising the regulation of craving via decrements to prefrontal function. To test our novel model and evaluate these alternative hypotheses we will administer the ROC task to 84 nicotine-dependent smokers, and 84 matched healthy controls during a 90-minute fMRI session. We will use threat of electric shock, which is known to induce acute stress on half of the trials. Then, we will compare (a) self-report and (b) neural activity between craving and regulation conditions, in a 2x2x2 factorial design: 2 ROC conditions (Craving vs. Regulation) x 2 Stress conditions (Threat of Shock vs. Safe from Shock) x 2 Stimulus types (Cigarettes vs. Appetitive Food control). To establish the clinical relevance of our findings, we will assess the contribution of each effect (Stress on Craving vs. on Regulation) to smoking severity. Finally, we will preliminarily explore gender and individual differences in stress, craving, and the regulation of craving, as evidence suggests they may moderate effects of stress and craving, with implications for smoking cessation. This project promises to advance our neurobiological understanding of stress, craving, and the regulation of craving, as well as their interaction and contribution to smoking. I turn, this would provide both a new theoretical framework to understand extant data on stress and substance use, and also adapt current treatments to specifically address the effects of stress of craving and its regulation.