The dopamine transporter in eating disorders: Uncovering new therapeutic targets

描述（由申请人提供）：虽然饮食失调是复杂的，其病因尚不清楚，多巴胺神经传递失调是一个一致的发现。多巴胺转运蛋白（DAT）是多巴胺神经传递的重要调节因子。DAT通过从细胞外液中摄取多巴胺来终止多巴胺神经传递，因此DAT是多巴胺信号强度和持续时间的主要决定因素。尽管它在维持多巴胺稳态中起着至关重要的作用，但目前还没有研究表明它本身在饮食失调中的功能。利用神经化学、细胞和行为方法，我们已经证明了DAT活动对饮食和食物摄入高度敏感，有力地支持了DAT活动在饮食失调患者中失调的观点。然而，迄今为止的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十几岁的女孩中最常见。在我们对DAT的基本理解中，缺乏的是它的活动如何随着年龄和性别的变化而变化，更重要的是，年龄和性别如何相互作用，导致“饮食失调”。那么，异常的DAT活动是如何导致“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“饮食失调”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关键特征，包括饥饿时食物摄入量减少、体重减轻、多动和胰岛素敏感性增加。重要的是，在这个模型中，大鼠必须在进食和另一种有益的条件——运动——之间“做出选择”。因此，食物摄入是由大鼠控制的，而不是由实验者人为控制的，这提供了一个强大的转化模型系统。我们将探索磷脂酰肌醇3-激酶（PI3K）和细胞外信号调节蛋白激酶（ERK），这些DAT活性的调节因子，我们已经确定为恢复正常DAT功能的假设靶点，作为治疗干预预防或减轻ABA严重程度的新靶点。考虑到多巴胺在奖励和动机中的作用，这些研究不仅将提供多巴胺神经传递失调在饮食失调中的机制洞察，而且还将提供其他疾病，包括成瘾和抑郁，这些疾病通常与饮食失调共病。

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.