Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Int J Obes (Lond). 2013 Aug;37(8):1095-103. doi: 10.1038/ijo.2012.178. Epub 2012 Nov 20.
A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity.
To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure.
Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively.
Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO.
Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that motivation for high-fat food, but not impulsive behavior, predicts the development of obesity, whereas decreases in striatal DAT function are exhibited only after the development of obesity.
使用饮食诱导肥胖（DIO）大鼠模型来确定多巴胺转运体（DAT）功能、冲动性和动机作为神经行为学结果和肥胖的预测指标。
通过 8 周高脂肪饮食（HF）暴露评估 DIO 发展后神经行为学的改变，确定纹状体 D2 受体密度、DAT 功能和表达、细胞外多巴胺浓度、冲动性和高脂肪强化物的动机。为了确定 DIO 的预测指标，在 8 周 HF 暴露之前评估神经行为学的先验因素，包括冲动性、高脂肪强化物的动机、DAT 功能和细胞外多巴胺。
通过体外动力学分析 [(3)H]raclopride 结合来确定纹状体 D2 受体密度。通过体外动力学分析 [(3)H]多巴胺摄取、甲基苯丙胺诱导的 [(3)H]多巴胺溢出和体内微透析无净流量来确定 DAT 功能。通过生物素化和 Western blot 确定 DAT 细胞表面表达。使用延迟折扣任务和渐进比率方案分别确定冲动性和食物动机行为。
与肥胖抵抗（OR）大鼠相比，肥胖易感性（OP）大鼠在 8 周 HF 饮食暴露后体重增加 18%，纹状体 D2 受体密度降低 42%，总 DAT 表达降低 30%，体外和体内 DAT 功能降低 40%，细胞外多巴胺增加 45%，甲基苯丙胺诱导的 [(3)H]多巴胺溢出增加两倍。OP 大鼠对食物的动机更高，令人惊讶的是，相对于 OR 大鼠，冲动性更低。冲动性、体内 DAT 功能和细胞外多巴胺浓度不能预测 DIO。重要的是，高脂肪强化物的动机预测了 DIO 的发展。
人类研究受到其确定冲动性、动机和 DAT 功能是 DIO 的原因还是后果的能力的限制。目前的动物模型表明，高脂肪食物的动机，但不是冲动行为，预测肥胖的发展，而纹状体 DAT 功能的降低仅在肥胖发展后才表现出来。
