The dopamine transporter in eating disorders: Uncovering new therapeutic targets

描述(申请人提供)：虽然进食障碍是复杂的，其病因尚不清楚，但多巴胺神经传递的失调是一个一致的发现。多巴胺神经传递的一个重要调节因子是多巴胺转运体(DAT)。DAT通过从细胞外液中摄取多巴胺来终止多巴胺的神经传递，因此DAT是多巴胺信号强度和持续时间的主要决定因素。尽管DAT在维持多巴胺动态平衡方面起着关键作用，但还没有关于DAT本身在饮食失调中的作用的研究。使用神经化学、细胞和行为方法，我们已经证明DAT活动对饮食和食物摄入量高度敏感，有力地支持了DAT活动在饮食障碍患者中调节失调的观点。然而，到目前为止，研究都是在成年雄性啮齿动物身上进行的。厌食症、暴食症和暴饮暴食在少女中最为常见。我们对DAT的基本了解不足的是，它的活动如何随着年龄和性别的变化而变化，以及重要的是，年龄和性别是如何相互作用，导致“饮食失调”的。反过来，DAT活性异常是如何导致“饮食失调”的呢？在这里，我们将开始填补这些关键的知识空白。我们将利用大鼠的“基于活动的厌食症”(ABA)模型来确定年龄、性别和“进食障碍”如何影响DAT功能，以及DAT活动的操纵如何改变饮食行为。ABA模型概括了人类厌食症的主要特征，包括饥饿、体重减轻、多动和胰岛素敏感性增加时的食物摄入量减少。重要的是，在这个模型中，老鼠必须在饮食和另一种有益的条件--锻炼--之间做出“选择”。因此，食物摄入量是由大鼠控制的，而不是由实验者人工控制的，这提供了一个强大的翻译模型系统。我们将探索磷酸肌醇3-激酶(PI3K)和细胞外信号调节蛋白激酶(ERK)这两种DAT活性的调节因子，我们已经确定它们是恢复正常DAT功能的假定靶点，作为预防或减轻ABA严重性的治疗干预的新靶点。鉴于多巴胺在奖赏和动机中的作用已经得到证实，这些研究不仅将为饮食障碍中多巴胺神经传递的失调提供机械性的洞察，还将为其他疾病提供机制上的洞察，包括成瘾和抑郁，这些疾病通常与饮食障碍并存。

DESCRIPTION (provided by applicant): Although eating disorders are complex and their etiology unclear, dysregulation of dopamine neurotransmission is a consistent finding. A vital regulator of dopamine neurotransmission is the dopamine transporter (DAT). DAT terminates dopamine neurotransmission by uptake of dopamine from extracellular fluid and because of this DAT is a primary determinant of both the strength and duration of dopamine signaling. In spite of its critical role in maintaining dopamine homeostasis, there have been no investigations of DAT function, per se, in eating disorders. Using neurochemical, cellular and behavioral approaches, we have shown that DAT activity is highly sensitive to diet and food intake, strongly supporting the notion that DAT activity is dysregulated in individuals with eating disorders. However, studies so far have been in adult, male rodents. Anorexia, bulimia and binge eating are most common in teenage girls. What is lacking in our fundamental understanding of DAT is how its activity varies as a function of age and sex and, importantly, how age and sex interact to contribute to "disordered eating". In turn, how does aberrant DAT activity contribute to "disordered eating"? Here we will begin to fill these critical knowledge gaps. We will make use of the "activity-based anorexia" (ABA) model in rats to determine how age, sex and "eating disorder" influence DAT function and how manipulations of DAT activity modify eating behavior. The ABA model recapitulates key characteristics of anorexia in humans, including reduced food intake in the presence of hunger, weight loss, hyperactivity, and increased insulin sensitivity. Importantly, in this model rats must "choose" between eating and another rewarding condition, exercise. Thus, food intake is controlled by the rat and not artificially by the experimenter, offering a powerful translational model system. We will explore phosphotidylinositol 3-kinase (PI3K) and extracellular signal-regulated protein kinase (ERK), regulators of DAT activity that we have identified as putative targets to restore normal DAT function, as novel targets for therapeutic intervention to prevent, or lessen the severity of ABA. Given the well-established role of dopamine in reward and motivation, these studies will not only provide mechanistic insight into dysregulation of dopamine neurotransmission in eating disorders, but also other illnesses, including addiction and depression, which are often co-morbid with eating disorders.