Role of the Endocannabinoid System in Compulsive Eating

描述(申请人提供)：流行性饮食障碍和肥胖，就像吸毒一样，可以被概念化为慢性复发条件，并交替出现禁欲(例如，为了避免“违禁”食物而节食)和复发(无法控制地吃可口的食物)，尽管有负面后果，但仍在继续。美味食品和节食的增加被认为是危险因素。进食障碍和肥胖经常与焦虑和情绪障碍并存，但这两种病理疾病之间的神经生物学联系却知之甚少。申请人最近对强迫性进食和共病的焦虑和情感障碍的病因提出了一种新的解释：过量进食可能是由与其缺失相关的负面情绪状态产生的(类似于过量服药和复发)。在这种背景下，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了作用，人们认为它的激活是反对焦虑的负反馈系统的一部分。我们的初步证据表明，杏仁核延长区的内源性大麻素系统是在禁食美味食物的过程中被招募的。因此，这里的一般假设是，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美味食物的摄入，并对抗美味食物退出的负面情感后果。本申请使用综合的行为学、药理学和分子方法来研究i)内源性大麻素系统在强迫性进食的消耗性和激励性成分中的作用，ii)将强迫性进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方面所起的作用，iii)扩展的杏仁核中内源性大麻素机制的神经适应性变化，其有助于强制进食的负面强化机制。 与公共健康的相关性：这些实验将提供有关大脑变化的关键信息，这些变化伴随着强迫性进食美味的食物，以及它们在并发焦虑和情绪障碍的发展中的相关性。这些信息对于开发更有效的饮食失调和肥胖症治疗方法非常重要。

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.