Effects of dietary obesity on midbrain dopamine systems

描述(由申请者提供)：尽管最近饮食肥胖的流行比例很高，但对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，我们仍然缺乏相当大的了解。一个根本的问题是，饮食肥胖对中枢神经系统功能的影响是由于体重和身体新陈代谢的变化，还是由于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的反应，如滥用的食物或药物。在这项提案中，我们将考虑一种假设，即长期接触自助餐厅式的美味饮食(导致体重过度增加)显著减少成年大鼠伏隔核和中脑多巴胺细胞体(如内侧前额叶皮质和纹状体)的其他目标的基础和诱发的多巴胺释放。我们还预测，基础和诱发多巴胺释放的这种减弱将降低美味食物的多巴胺释放效率，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增强剂(如精神刺激剂)的摄入量，以实现与正常体重动物相当的多巴胺释放。此外，我们预测，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一个标志。我们的具体目标如下： A.通过体内微透析，确定饮食肥胖(由自助餐厅式饮食与高脂肪饮食与高碳水化合物饮食引起)对成年大鼠中脑多巴胺系统(中隔隔核、黑质纹状体、边缘皮质)所有主要通路(中隔隔核、黑质纹状体、边缘皮质)的基础、膳食和精神刺激剂挑战的多巴胺神经化学的选择性影响。多巴胺释放的变化与行为的变化(运动、饮食消耗、注射阿片类拮抗剂纳洛酮的反应)相关。将结果与近亲繁殖了几代的老鼠进行比较，这些老鼠要么容易肥胖，要么抵抗肥胖。 B.用急性切片安培法实时识别饮食肥胖对成年大鼠中脑多巴胺系统(中隔隔核、黑质纹状体、边缘皮质)所有主要通路中电刺激诱发的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、饮食肥胖、近亲繁殖的肥胖倾向和近亲繁殖的肥胖抵抗动物的切片。 C.使用近亲交配的肥胖倾向和肥胖抵抗新生大鼠的腹侧被盖区多巴胺神经元培养，在实际接触可口饮食和过度体重增加之前，考虑肥胖抵抗动物的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