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.
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