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，但关于肥胖对参与动机和食物奖励的中脑多巴胺投射的神经化学作用的知识相当缺乏。一个根本的问题是饮食性肥胖对中枢神经系统功能的影响是否是由于体重和身体代谢的变化;或者由于高能量饮食的适口性，这可能会显着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的反应，如滥用食物或药物。在这个提议中，我们将考虑这样的假设，即长期暴露于一种可口的饮食（导致过度的体重增加）显着减少基础和诱发多巴胺释放的成年大鼠延髓核和其他目标的中脑多巴胺细胞体（如内侧前额叶皮层和纹状体）。我们还预测，这种基础和诱发多巴胺释放的衰减将降低可口食物的多巴胺释放功效，并诱导肥胖动物增加可口食物或其他非生理性多巴胺释放抑制剂（如精神兴奋剂）的摄入，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的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： A.通过体内微透析，确定饮食性肥胖（由高脂饮食与高碳水化合物饮食诱导）对成年大鼠中脑多巴胺系统（中脑、黑质纹状体、皮质边缘）所有主要通路中基础、膳食和精神兴奋剂激发的多巴胺神经化学的选择性影响。将多巴胺释放的变化与行为变化（运动、饮食消耗、对阿片拮抗剂纳洛酮注射的反应）相关联。将结果与近亲繁殖几代的容易肥胖或抗肥胖大鼠的结果进行比较。 B。急性切片电流分析法确定饮食性肥胖对成年大鼠中脑多巴胺系统（中脑、黑质纹状体、皮质边缘）所有主要通路中真实的时间电刺激诱发多巴胺释放的选择性影响。研究肥胖对神经递质释放和再摄取的不同影响。比较正常体重、饮食性肥胖、近交系肥胖倾向和近交系抗肥胖动物的切片。 C.使用来自近亲繁殖的饮食性肥胖倾向和肥胖抵抗的新生大鼠的培养的腹侧被盖区多巴胺神经元来考虑在实际暴露于可口的饮食和过度的体重增加之前，在肥胖抵抗的动物中多巴胺量子释放是否更高

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