Neurobiology of compulsive eating.

描述（由申请人提供）：在过去的几十年里，饮食失调和肥胖的流行蔓延提出了一个问题，即某些非常美味的食物是否可能导致“食物依赖”的发展。事实上，流行的饮食失调和肥胖，就像药物成瘾一样，可以被定义为慢性复发的情况，在禁食（例如，节食以避免“禁止”的食物）和复发（无法控制地吃美味的食物）交替的时期，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并存；然而，这两种病理状况之间的神经生物学联系尚不清楚。我们最近提出了一种新的可靠的可口食物依赖动物模型，有助于理解强迫进食和共病焦虑和情感障碍的病因。强迫性进食可能是由于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，以及在戒断期间出现的消极情绪状态，类似于戒断滥用药物。因此，依赖于一般的假设，即戒断会产生可口的食物暴饮暴食，作为一种“自我治疗”的形式，拟议的应用将调查强迫饮食与共病焦虑和情绪障碍之间的关系。具体而言，所提出的特定目标的实验使用行为，药理学和分子的结合方法来阐明：i) CRF1受体拮抗剂对强迫进食的完善，情绪和动机成分的药理作用的重要脑部位；ii)急性轻度应激对食物消耗、情感、HPA和CRF反应的影响，在长期禁食期间有美味饮食循环史的动物中；iii) CRF/CRF1系统在大脑奖励系统的适应和由美味饮食变化引起的抑郁样行为中的作用。本研究将从负强化的角度阐明强迫进食与共病焦虑和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。

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.