Effects of dietary obesity on midbrain dopamine systems

饮食肥胖对中脑多巴胺系统的影响

• 批准号: 7061335
• 负责人: EMMANUEL N POTHOS
• 金额: $ 32.73万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-02 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061335
• 关键词: behavioral /social science research tag; body physical activity; caloric dietary content; central nervous system stimulants; diet; dietary carbohydrates; dietary lipid; dopamine; electrostimulus; genetic susceptibility; laboratory rat; membrane transport proteins; mesencephalon; microdialysis; motivation; naloxone; neural plasticity; neurochemistry; neurotransmitter transport; nutrient intake activity; nutrition related tag; obesity; pathogenic diet; tissue /cell culture; tyrosine 3 monooxygenase

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

描述（由申请人提供）：尽管最近饮食肥胖的流行比例，但对肥胖对涉及动机和食物奖励涉及的中脑多巴胺预测的神经化学作用的知识很大。一个基本问题是饮食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所致。或者由于高能饮食的可容纳性，可能会显着改变中脑多巴胺系统中的突触可塑性，并改变其对多巴胺释放剂的反应，例如食物或滥用药物。在这一提案中，我们将考虑以下假设：长期暴露于自助餐厅型可口饮食（导致体重增加过度）会大大降低基础，并诱发成年大鼠核酸核的多巴胺释放，以及其他中脑多巴胺细胞体的其他靶标（例如中间脑前颈前乳状细胞前皮质和脊髓乳状细胞膜和脊髓片）。我们还预测，这种基础和诱发的多巴胺释放中的这种衰减将降低多巴胺释放可口餐的功效，并诱使肥胖动物增加可口食品的摄入量或其他非生理多巴胺释放的增强剂（如心理刺激剂），以实现多巴胺释放可比性的动物。此外，我们预测，产后年龄的早期中央多巴胺系统中诱发的多巴胺信号的增加是肥胖耐药性的标志。我们的具体目标如下： A.确定饮食肥胖症的选择性影响（由自助于其饮食与高脂饮食与高碳水化合物饮食与高碳水化合物饮食诱导）对成人多巴胺多巴胺系统的所有主要途径（MesoAcccccccccccccecent in migrosirim inir congrip iniv iniv iniv iniv iniv iniv iniv inim contrication to to high High-Carbohydrate饮食）对基础，进餐和心理刺激性的多巴胺神经化学的基础，饮食和心理刺激性挑战者的饮食。微透析。多巴胺释放的变化与行为变化（运动，饮食消耗，对鸦片拮抗剂纳洛酮的注射的反应）的变化。将结果与几代人近交的大鼠的结果进行比较，使其易于肥胖或抗肥胖。 B.在成年大鼠中脑多巴胺系统（Mesoaccumbens，nigrostriatal，Corticolimbic）均使用急性切片计量法的所有主要途径中，在所有主要途径中，确定饮食肥胖对电刺激诱发的多巴胺释放的选择性作用。研究肥胖对神经递质释放与再摄取的差异影响。比较从正常体重，饮食肥胖，近交性肥胖和近交性肥胖动物中的切片。 C.使用含有杂交饮食饮食肥胖和耐肥胖的新生儿大鼠的培养的腹腹换胸膜神经元，以考虑在实际暴露于可口饮食之前耐肥胖动物的多巴胺量释放是否更高，并且体重增加过多