Kappa Opioid Receptor Imaging in Anorexia

描述(申请人提供)：神经性厌食症(AN)是一种严重的精神疾病，具有两个主要特征：(A)与进食相关的强烈厌恶导致难以保持健康的体重；(B)与避免进食、进食或体重增加相关的快乐。动力-奖励系统的紊乱在活跃的AN患者中被很好地记录下来，甚至在那些体重恢复(AN-REC)的AN患者中也是如此。从理论上讲，特质焦虑和避免伤害的障碍与血清素和多巴胺的障碍有关。然而，进食行为受到阿片系统的严格控制，特别是在压力条件下。我们的提案测试了一种关于压力作用的新理论 而内源性阿片类药物作用于AN的主要特征。AN的饥饿特征在疾病的早期阶段作为一种慢性应激源增加内源性阿片类药物。然而，阿片系统适应了这种长期的压力，并创造了一个独特的阿片系统，其功能很像成瘾中的戒断状态。对成瘾的研究表明，kappa-阿片受体介导了药物依赖者应激诱导的复发。因此，我们将饥饿概念化为药物，将AN-REC定义为AN过程中的撤退状态。这个模型为为什么AN患者的复发率如此之高提供了一个可检验的假说。我们将招募7名最近(1岁)从AN恢复体重的成年女性和7名健康的年龄和体重匹配的对照组(HCS)参加一项PET研究，使用一种新的Kappa-阿片受体(KOR)PET示踪剂。受试者将完成避免食物的实验室测量和基于食物奖励的反转学习任务。我们有三个具体的目标：(1)测试An-REC和HCS之间KOR密度的群体差异；(2)测试脑岛、杏仁核和下丘脑的KOR密度与实验室和食物回避自我报告测量之间的相关性；(3)测试动机-奖励回路中的KOR密度与反向学习任务中的表现和情绪的心理生理指标之间的相关性。应激激素和阿片肽(ACTH、皮质醇、β-内啡肽)将用于探索性分析AN-REC和HC之间糖皮质激素功能和KOR水平的关系。这项研究的结果将用于确定可用于预防AN-REC患者复发的新药物治疗方法，并确定可能有助于解释AN患者复发风险的生物标记物。

DESCRIPTION (provided by applicant): Anorexia nervosa (AN) is a serious mental illness that is characterized by two primary features: (a) intense disgust associated with eating leading to difficulty maintaining healthy weight, (b) pleasure associated with avoidance of food, eating, or weight gain. Disturbances in the motivation-reward system are well documented in patients with active AN and even in those with AN who have achieved weight restoration (AN-REC). Disturbances in trait anxiety and harm avoidance have been theoretically linked to disturbances in serotonin and dopamine. However, eating behavior is tightly regulated by the opioid system particularly under conditions of stress. Our proposal tests a novel theory about the role of stress and endogenous opioid function in the primary features of AN. Starvation characteristic of AN acts as a chronic stressor elevating endogenous opioids in the early stages of the illness. However, the opioid system adapts to this chronic stress and creates a unique opioid system that functions much like a withdrawal state found in addiction. Research on addictions suggests that the kappa-opioid receptor mediates stress induced relapse among drug dependent individuals. Thus, we conceptualize starvation as the drug and AN-REC as the withdrawal state in the course of AN. This model provides a testable hypothesis for why relapse rates among those with AN are so high. We will recruit 7 adult medication free women recently (< 1 yr) weight restored from AN and 7 healthy age and weight matched controls (HCs) to participate in a PET study using a novel PET tracer for the Kappa-opioid receptor (KOR). Subjects will complete laboratory measures of food avoidance and a food-reward based reversal learning task. We have three specific aims: (1) To test for group differences in the density of KORs between AN-REC and HCs; (2) To test the correlations between KOR density in insula, amygdala, and hypothalamus and laboratory and self-report measures of food avoidance; (3) To test the correlations between KOR density in motivation- reward circuits and performance on a reversal learning task and psychophysiological measures of emotion. Stress hormones and opioid peptides (ACTH, cortisol, beta-endorphin) will be measured in an exploratory analysis of the relationship between glucocorticoid function and KOR levels among AN-REC and HC. Results from this study will be used to identify novel pharmacological treatments that may be used to prevent relapse among AN-REC patients and identify biomarkers that may help explain relapse risk among those with AN.