Neurobiology of compulsive eating.

描述（由申请人提供）：在过去的几十年中，饮食失调和肥胖症的流行蔓延提出了一个问题，即某些非常可口的食物是否可能导致“食物依赖”的发展。事实上，流行性饮食失调和肥胖症，像药物成瘾一样，可以被概念化为具有交替禁欲期的慢性复发性疾病（例如，节食以避免“禁止”食物）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。饮食失调和肥胖经常与焦虑和情绪障碍共存;然而，人们对这两种病理状况之间的神经生物学联系知之甚少。我们最近提出了一个新的可靠的动物模型可口的食物依赖，有助于了解强迫性进食和共病的焦虑和情感障碍的病因。强迫性进食可能是由下丘脑外促肾上腺皮质激素释放因子（CRF）脑应激系统的募集和戒断期间出现的负面情绪状态（类似于从滥用药物中戒断）产生的。因此，依赖于一般假设，即戒断产生可口的食物暴饮暴食作为一种形式的“自我治疗”，拟议的应用程序将调查强迫性进食和共病焦虑和情绪障碍之间的关系。具体而言，拟定特定目的的实验使用了行为、药理学和分子学相结合的方法来阐明：i）CRF 1受体拮抗剂对强迫性进食的消耗、情感和动机成分的药理学作用的重要脑部位; ii）急性轻度应激对食物消耗、情感以及HPA和CRF反应的影响，在长期禁欲期间有美味饮食循环史的动物中; iii）CRF/CRF 1系统在大脑奖励系统的适应中以及在美味饮食交替诱导的抑郁样行为中的作用。本研究将透过负强化的透镜，阐明强迫性进食与共病焦虑及情绪障碍之间的神经生物学关系。更好地了解强迫性饮食的病因将有助于预防饮食失调和肥胖的发生，并将增加对数千万人进行药物干预的可能性。 公共卫生相关性：这些实验将提供有关强迫性进食可口食物的神经生物学基质的关键信息，以及它们在压力敏感性和共病焦虑和情绪障碍发展中的相关性。这些信息对于理解进食障碍和肥胖症的病因以及开发更有效的药物治疗是重要的。

DESCRIPTION (provided by applicant): In the last decades, the epidemic spreading of eating disorders and obesity has raised the question whether certain highly palatable foods may be responsible for the development of a "food dependence". In fact, 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. Eating disorders and obesity very frequently occur comorbidly with anxiety and mood disorders; however the neurobiological link between the two pathological conditions is poorly understood. We have recently proposed a new reliable animal model of palatable food dependence which contributes to the understanding of the etiology of compulsive eating and comorbid anxiety and affective disorders. Compulsive eating may be generated by the recruitment of the extrahypothalamic corticotropin-releasing factor (CRF) brain stress systems and by the emergence of a negative emotional state during abstinence, analogous to withdrawal from abused drugs. Therefore, relying on the general hypothesis that withdrawal generates palatable food overeating as a form of "self-medication," the proposed application will investigate the relationship between compulsive eating and comorbid anxiety and mood disorders. Specifically, the experiments of the proposed Specific Aims use a combined behavioral, pharmacological and molecular approach to elucidate: i) the brain sites important for the pharmacological effects of CRF1 receptor antagonists on the consummatory, emotional and motivational components of compulsive eating; ii) the effects of acute mild stress on food consumption, affectivity, and HPA and CRF responses, in animals with a history of palatable diet-cycling during protracted abstinence; iii) the role of the CRF/CRF1 system in the adaptations of the brain reward system and in the depressive-like behavior induced by the palatable diet alternation. This proposal will elucidate the neurobiological relationship between compulsive eating and comorbid anxiety and mood disorders through the lens of negative reinforcement. A better understanding of the etiology of compulsive eating would help prevent the onset of eating disorders and obesity, and would increase the potential for pharmacological intervention for tens of millions of people. PUBLIC HEALTH RELEVANCE: These experiments will provide critical information about the neurobiological substrates of compulsive eating of palatable food, and their relevance in the development of stress sensitivity and comorbid anxiety and mood disorders. Such information is important for understanding the etiology of eating disorders and obesity and for the development of more efficacious pharmacological treatments.