Role of the Endocannabinoid System in Compulsive Eating

描述（由申请人提供）：流行性饮食失调和肥胖，如毒瘾，可以被概念化为慢性复发性疾病，具有交替的禁欲期（例如，节食以避免“禁止”食物）和复发（无法控制地吃美味食物），尽管有负面后果，但仍持续存在。美味食物的增加和节食被认为是危险因素。饮食失调和肥胖经常与焦虑和情绪障碍同时发生，但人们对这两种病理状况之间的神经生物学联系知之甚少。申请人最近对强迫性饮食以及共病焦虑和情感障碍的病因学提出了一种新的解释：暴饮暴食可能是由与其缺乏相关的负面情绪状态产生的（类似于过量摄入药物和复发）。在这种情况下，越来越多的证据表明内源性大麻素系统在享乐喂养中发挥着作用，并且人们相信它的激活是对抗焦虑的负反馈系统的一部分。我们的初步证据表明，在禁食美味食物期间，扩展杏仁核中的内源性大麻素系统被招募。因此，这里的一般假设是，扩展杏仁核内源性大麻素系统的神经适应通过负强化机制维持可口食物的摄入，并对抗可口食物戒断的负面情感后果。本申请使用综合行为、药理学和分子方法来研究i)内源性大麻素系统在强迫性饮食的完成和动机成分中的作用，ii)将强迫性饮食与焦虑和抑郁障碍联系起来的机制以及内源性大麻素系统在这种情况下所发挥的作用，iii)扩展杏仁核中的内源性大麻素机制的神经适应变化，这有助于负强化机制强迫性饮食。 公共健康相关性：这些实验将提供关于伴随强迫性进食美味食物而发生的大脑变化及其与共病焦虑和情绪障碍的发展的相关性的重要信息。这些信息对于开发更有效的饮食失调和肥胖治疗方法非常重要。

DESCRIPTION (provided by applicant): Epidemic eating disorders and obesity, like drug addiction, can be conceptualized as chronic relapsing conditions with alternating periods of abstinence (e.g., dieting to avoid "forbidden" foods) and relapse (uncontrollable eating of palatable foods) that continue despite negative consequences. The increased availability of palatable foods and dieting are believed to be risk factors. Eating disorders and obesity very frequently occur comorbidly with anxiety and mood disorders but the neurobiological link between the two pathological conditions is poorly understood. The applicant has recently proposed a new interpretation of the etiology of compulsive eating and comorbid anxiety and affective disorders: overeating may be generated by the negative emotional state associated with its absence (analogous to excessive intake of drugs and relapse). In this context, there is increasing evidence that the endocannabinoid system plays a role in hedonic feeding and it is believed that its activation is part of a negative feedback system that opposes anxiety. Our preliminary evidences show that the endocannabinoid system in the extended amygdala is recruited during abstinence from palatable food. Therefore, the general hypothesis here is that neuroadaptations in the endocannabinoid system in the extended amygdala sustain palatable food intake via a negative reinforcement mechanism and oppose the negative affective consequences of palatable food withdrawal. The present application uses an integrative behavioral, pharmacological and molecular approach to study i) the role of the endocannabinoid system in the consummatory and motivational components of compulsive eating, ii) the mechanisms which link compulsive eating to anxiety and depressive disorders and the role played by the endocannabinoid system in this context, iii) the neuroadaptational changes in the endocannabinoid machinery in the extended amygdala which contribute to the negative reinforcement mechanisms of compulsive eating. PUBLIC HEALTH RELEVANCE: These experiments will provide critical information about the brain changes that accompany compulsive eating of palatable food and their relevance in the development of comorbid anxiety and mood disorders. Such information is important for the development of more efficacious treatments for eating disorders and obesity.