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患有其他医学并发症，如肥胖和抑郁症。最近，已经开发了暴食的动物模型，其中大鼠间歇性地获得甜味和/或高脂肪食物。随着这种食物的消费量在几周内逐渐增加，观察到丘脑核（NAc）的神经化学变化，包括阿片受体表达的增加。初步实验表明，注射一种广谱阿片受体拮抗剂到NAC有更明显的影响甜/脂肪液体的消耗在暴饮暴食比对照组大鼠。这些结果表明，暴饮暴食可能是由于，至少部分，在NAC阿片类神经传递的上调。为了验证这一假设，我们将首先确定NAc中的三种阿片受体（μ，δ和κ）中的哪一种有助于食用可口的液体，以及这些贡献在暴食和对照大鼠中是否不同。我们还将确定这些贡献是否是特定的核心或外壳区域的NAC。此外，我们将确定NAc神经元的适口性编码是否与暴饮暴食大鼠的对照不同。最后，我们将测试的假设，内源性阿片类物质有助于NAc神经元的适口性编码，这种贡献是不同的暴饮暴食与对照动物。我们的目标是阐明暴饮暴食背后的神经机制，以便可以开发专门针对这些机制的暴饮暴食症药物治疗。因为同样的神经回路也参与了药物成瘾，我们的研究也将有助于理解成瘾的神经机制，以及一般的奖励寻求行为。

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.