Nucleus accumbens opioid-dependent mechanisms of binge eating

描述（由申请人提供）：神经性贪食症和暴食症（“暴食症”）是严重的公共卫生问题，部分原因是患有这些疾病的人往往还会遭受其他医学并发症，如肥胖和抑郁。最近，暴饮暴食的动物模型已经被开发出来，在这些模型中，老鼠被间歇性地提供甜食和/或高脂肪食物。随着这种食物的摄入量在几周内不断增加，可以观察到伏隔核（NAc）的神经化学变化，包括阿片受体的表达增加。初步实验表明，在NAc中注射广谱阿片受体拮抗剂对暴饮暴食中的甜味/脂肪液体消耗的影响比对照大鼠更明显。这些结果表明，暴饮暴食可能是由于，至少部分是由于NAc中阿片能神经传递的上调。为了验证这一假设，我们将首先确定NAc中三种阿片受体（mu， delta和kappa）中的哪一种对美味液体的消耗有贡献，以及这些贡献在暴饮暴食和对照大鼠中是否不同。我们还将确定这些贡献是特定于NAc的核心区域还是壳区域。此外，我们将确定NAc神经元对适口性的编码是否与暴饮暴食大鼠的对照组不同。最后，我们将测试内源性阿片类物质有助于NAc神经元的适口性编码的假设，并且这种贡献在暴饮暴食与对照动物中是不同的。我们的目标是阐明暴饮暴食背后的神经机制，这样就可以开发出专门针对暴饮暴食机制的药物治疗方法。因为同样的神经回路也涉及药物成瘾，我们的研究也将有助于理解成瘾的神经机制，以及一般的寻求奖励行为。

DESCRIPTION (provided by applicant): Bulimia nervosa and binge eating disorder ("binge eating disorders") are serious public health problems, in part because people with these disorders tend also to suffer other medical complications, such as obesity and depression. Recently, animal models of binge eating have been developed, in which rats are provided intermittent access to sweet and/or high fat food. As consumption of this food escalates over several weeks of access, neurochemical changes in the nucleus accumbens (NAc) are observed, including increases in expression of opioid receptors. Pilot experiments show that injection of a broad-spectrum opioid receptor antagonist into the NAc has more pronounced effects on sweet/fat liquid consumption in binge eating than in control rats. These results suggest that binge eating could be due, at least in part, to upregulation of opioidergic neurotransmission in the NAc. To test this hypothesis, we will first determine which of three opioid receptors (mu, delta and kappa) in the NAc contributes to consumption of palatable liquid, and whether these contributions are different in binge eating and control rats. We will also determine whether these contributions are specific to the core or shell regions of the NAc. In addition, we will determine whether encoding of palatability by NAc neurons differs from controls in binge eating rats. Finally, we will test the hypotheses that endogenous opioids contribute to palatability encoding by NAc neurons, and that this contribution is different in binge eating vs control animals. Our goal is to elucidate the neural mechanisms that underlie binge eating, so that pharmaceutical treatments for binge eating disorders can be developed that specifically target these mechanisms. Because the same neural circuits are involved in drug addiction, our studies will also contribute towards understanding the neural mechanisms of addiction, and of reward-seeking behavior in general. PUBLIC HEALTH RELEVANCE: Approximately 5% of the American population suffers, during at least part of adult life, from binge eating disorder or bulimia nervosa ("binge eating disorders"); these are serious public health problems because of the associated medical complications such as depression and obesity. The research proposed here will use an animal model of binge eating to help us understand how brain circuits that are critical for reward-seeking and feeding control these behaviors, and how circuit activity changes to produce binge eating. Identifying specific neural mechanisms responsible for binge eating will potentially stimulate the development of pharmacological interventions that specifically target these mechanisms to treat binge eating disorders.