Dopamine mechanisms in development of type-2 diabetes

描述（由申请人提供）：肥胖引起或加重许多慢性疾病，最明显的是非胰岛素依赖型糖尿病（NIDDM）。大多数肥胖是由适度的，但长期暴饮暴食。大冢长仓德岛脂肪（OLETF）大鼠，缺乏CCK-A受体，贪食，肥胖，并逐渐发展为NIDDM。在OLETF大鼠中，增加的食物摄入是肥胖发展所必需的，这表明NIDDM继发于糖尿病前期的摄食过多。因此，OLETF大鼠是人类中最普遍的NIDDM形式的合理模型。该品系慢性摄食过多的根本原因尚不清楚，不能完全由其外周饱食缺陷解释。相反，对控制膳食量至关重要的中枢通路功能障碍是最有可能的原因。在这个项目中，OLETF大鼠被用来研究在2型糖尿病的发展过程中，在中枢动机系统内的多食行为表型和多巴胺（DA）信号之间的关系。我们建议，改变多巴胺能功能的中脑多巴胺（DA）系统有助于在OLETF大鼠暴饮暴食，增加偏好的orosensory刺激作用，通常首选的食物。 将采用行为学、神经化学和组织学方法来挑战这一假设。本申请有四个具体目标：1）表征基础多巴胺能表型（2）通过研究糖尿病前期OLETF大鼠的营养偏好功能（基于其口腔感觉和吸收后特性）来表征过度进食行为表型; 3）通过比较糖尿病前期OLETF和年龄和体重匹配的非突变对照（LETO）大鼠之间优选的蔗糖或脂肪溶液的假喂养的影响来评估行为和DA信号传导之间的关系; 4）通过使用精神兴奋剂哌醋甲酯的长期治疗来逆转对蔗糖和脂肪的偏好和摄入，并延迟OLETF大鼠中糖尿病的发作，来解决关系的因果关系。这些研究将有助于确定多巴胺能系统的可塑性如何影响与摄食过多和饮食诱导的NIDDM发展相关的行为和代谢因素。

DESCRIPTION (provided by applicant): Obesity causes or exacerbates many chronic illnesses, most notably non-insulin-dependent diabetes mellitus (NIDDM). Most obesity is caused by modest, but chronic overeating. Otsuka Long-vans Tokushima fatty (OLETF) rats, which lack the CCK-A receptor, are hyperphagic, obese, and gradually develop NIDDM. In OLETF rats, increased food intake is necessary for the development of obesity, suggesting that the NIDDM is secondary to the prediabetic hyperphagia. Thus, OLETF rats are reasonable model of the most prevalent form of NIDDM in humans. The underlying cause of the chronic hyperphagia in this strain is unknown and cannot be explained entirely by their peripheral satiation deficits. Rather, a dysfunction in central pathways critical to the control of meal size is the most likely contributor. In this project, OLETF rats are used to study the relationship between the hyperphagic behavioral phenotype and dopamine (DA) signaling within the central motivational system during the development of type-2 diabetes. We propose that altered dopaminergic functioning in the mesoaccumbens dopamine (DA) system contributes to the overeating in OLETF rats by increasing preference for the orosensory stimulatory effects of normally preferred foods. Behavioral, neurochemical and histological methods will be employed to challenge this hypothesis. The application has four specific aims: 1) to characterize the basic dopaminergic phenotype (basal and stimulated DA release and reuptake) of the OLETF rats at three ages, reflecting the development of diabetes; 2) to characterize hyperphagic behavioral phenotype by investigating nutrient preference functions in prediabetic OLETF rats based on their orosensory and postabsorbtive properties; 3) to assess the relationship between behavior and DA signaling by comparing the effects of sham-feeding of preferred sucrose or fat solutions between prediabetic OLETF and age- and body weight-matched non-mutant control (LETO) rats; 4) to address causality of the relationship by using chronic treatment of the psychostimulant methylphenidate to reverse preference for and intake of sucrose and fat, and to delay onset of diabetes in OLETF rats. These studies will help determine how plasticity in the dopaminergic system affects behavioral and metabolic factors related to hyperphagia and the development of dietary-induced NIDDM.