Effects of dietary obesity on midbrain dopamine systems

描述（由申请人提供）：尽管最近饮食性肥胖的流行比例，但关于肥胖对涉及动机和食物奖励的中脑多巴胺投射的神经化学影响的知识相当缺乏。一个基本的问题是饮食肥胖对中枢神经系统功能的影响是否由于体重和身体代谢的变化；或者是因为高能量饮食的适口性，这可能会显著改变中脑多巴胺系统的突触可塑性，并改变它们对多巴胺释放剂（如食物或滥用药物）的反应。在这个提议中，我们将考虑这样一个假设，即长期暴露于自助餐厅式的美味饮食（导致体重过度增加）会显著减少成年大鼠伏核和中脑多巴胺细胞体的其他目标（如内侧前额叶皮层和纹状体）的基础和诱发多巴胺释放。我们还预测，这种基础多巴胺和诱发多巴胺释放的衰减将降低美味食物的多巴胺释放效果，并诱导肥胖动物增加美味食物或其他非生理性多巴胺释放强化物（如精神兴奋剂）的摄入量，以达到与正常体重动物相当的多巴胺释放。此外，我们预测，在出生后早期，中枢多巴胺系统中诱发多巴胺信号的增加是肥胖抵抗的标志。我们的具体目标如下：

DESCRIPTION (provided by applicant): Despite recent epidemic proportions of dietary obesity, there is a considerable lack of knowledge about the neurochemical effects of obesity on those midbrain dopamine projections involved in motivation and food reward. A fundamental issue is whether the effects of dietary obesity on CNS function are due to changes in body weight and bodily metabolism; or due to the palatability of high-energy diets, which could significantly alter synaptic plasticity in midbrain dopamine systems and change their response to dopamine-releasing agents, such as food or drugs of abuse. In this proposal we will consider the hypothesis that chronic exposure to a cafeteria-type palatable diet (leading to excessive weight gain) significantly reduces basal and evoked dopamine release in the adult rat nucleus accumbens and other targets of the midbrain dopamine cell bodies (such as the medial prefrontal cortex and the striatum). We also predict that this attenuation in basal and evoked dopamine release would reduce the dopamine-releasing efficacy of palatable meals and induce obese animals to increase the intake of palatable food or other non-physiological dopamine-releasing reinforcers (like psychostimulants) in order to achieve dopamine release comparable to that of a normal weight animal. Furthermore, we predict that an increase in evoked dopamine signal in central dopamine systems early in postnatal age is a marker for obesity resistance. Our specific objectives are as follows: A. Identify selective effects of dietary obesity (induced by a cafeteria-type diet versus a high-fat diet versus high-carbohydrate diet) on basal, meal- and psychostimulant-challenged dopamine neurochemistry in all major pathways of the adult rat midbrain dopamine system (mesoaccumbens, nigrostriatal, corticolimbic) with in vivo microdialysis. Correlate changes in dopamine release with changes in behavior (locomotion, diet consumption, response to injections of the opiate antagonist naloxone). Compare results with those on rats inbred for several generations to be either obesity-prone or obesity-resistant. B. Identify selective effects of dietary obesity on electrical stimulation-evoked dopamine release in real time in all major pathways of the adult rat midbrain dopamine system (mesoaccumbens, nigrostriatal, corticolimbic) with acute slice amperometry. Study differential effects of obesity on neurotransmitter release versus reuptake. Compare slices from normal weight, dietary obese, inbred obesity-prone and inbred obesity-resistant animals. C. Use cultured ventral tegmental area dopamine neurons from inbred dietary obesity-prone and obesity-resistant neonatal rats to consider whether dopamine quantal release is higher in obesity-resistant animals before actual exposure to palatable diets and excessive weight gain