Dopamine mechanisms in development of type-2 diabetes

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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.