CNS Dopamine as Marker for Obesity Predisposition: Link to Food and Drug Reward

中枢神经系统多巴胺作为肥胖倾向的标志:与食品和药物奖励的联系

基本信息

  • 批准号:
    7908875
  • 负责人:
  • 金额:
    $ 3.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-15 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Dietary obesity is a fast growing epidemic worldwide and effective approaches for addressing this public health problem are necessary. The involvement of hedonic aspects of feeding in the obesity epidemic is still unclear and its study may reveal common mechanisms that mediate susceptibility or resistance to natural and drug rewards. This proposal focuses on understanding the link between dietary obesity predisposition and central dopamine systems implicated in food and d-amphetamine rewards. We hypothesize (and so far have confirmed) that the inbred obesity-prone (OP) phenotype in the rat is characterized by low central dopamine tone and reduced dopamine response to stimuli like food and d-amphetamine. The reduced dopamine response may lead to compensation with increased laboratory chow or amphetamine intake. Proteins that downregulate the dopamine tone are potential novel markers of obesity predisposition. Appropriate interventions may alter the susceptibility of the OP phenotype to indulgent stimuli (like high-energy diets or psychostimulants) by fine-tuning central dopamine exocytosis. The specific aims of this proposal include considering: 1) how obesity predisposition is linked to dopamine release kinetics before and after body weight differences arise and before and after a meal or an amphetamine challenge 2) whether regulatory proteins of central dopamine exocytosis are markers for obesity predisposition 3) developmental and molecular interventions that alter the OP phenotype. Inbred OP and obesity-resistant (OR) rats will be used throughout as they develop a weight difference while on the same diet and allow for distinction from diet history-related effects. OP rats closely model human obesity predisposition through polygenic inheritance favoring weight gain. Following a multi-level approach, we propose to profile in vivo dopamine release and behavior; real-time dopamine exocytosis in the acute slice and primary cell culture; and mRNA and protein levels of regulators of dopamine exocytosis. Preliminary results show that adult outbred obese and inbred OP rats had lower basal, meal-challenged and amphetamine-challenged extracellular dopamine levels. Tyrosine hydroxylase mRNA levels were low in OP adults, while the vesicular monoamine transporter (VMAT2) protein levels were low in OP neonatal rat dopamine cell cultures. Proposed interventions to alter the OP phenotype and associated central dopamine neurotransmission include placement of OP litters with OR dames at day PO, VMAT2 over expression in the nucleus accumbens of OP rats, and pair feeding of OP and OR rats.
描述(由申请人提供):饮食性肥胖是一种快速增长的流行病,在全球范围内,解决这一公共卫生问题的有效方法是必要的。在肥胖流行中,进食的享乐方面的参与仍然不清楚,其研究可能揭示介导对自然和药物奖励的易感性或抵抗性的共同机制。这项建议的重点是了解饮食性肥胖易感性和涉及食物和d-安非他明奖励的中枢多巴胺系统之间的联系。我们假设(到目前为止已经证实),大鼠的近亲繁殖肥胖倾向(OP)表型的特征是中枢多巴胺水平较低,并且对食物和d-苯丙胺等刺激的多巴胺反应降低。减少多巴胺反应可能导致补偿增加实验室食物或安非他明摄入量。下调多巴胺水平的蛋白质是肥胖易感性的潜在新标志物。适当的干预可能会改变OP表型的易感性放纵刺激(如高能量饮食或精神兴奋剂)通过微调中央多巴胺胞吐。该建议的具体目的包括考虑:1)肥胖倾向如何与体重差异出现前后以及进餐或安非他明激发前后的多巴胺释放动力学相关2)中枢多巴胺胞吐的调节蛋白是否是肥胖倾向的标志物3)改变OP表型的发育和分子干预。将始终使用近交OP和肥胖抵抗(OR)大鼠,因为它们在相同饮食下出现体重差异,并允许与饮食史相关效应区分开来。OP大鼠通过有利于体重增加的多基因遗传密切模拟人类肥胖倾向。多层次的方法之后,我们建议在体内多巴胺的释放和行为,实时多巴胺胞吐在急性切片和原代细胞培养,和多巴胺胞吐的调节剂的mRNA和蛋白质水平。初步结果表明,成年远交肥胖和近交OP大鼠有较低的基础,膳食挑战和安非他明挑战的细胞外多巴胺水平。酪氨酸羟化酶mRNA水平低,OP成人,而囊泡单胺转运蛋白(VMAT 2)蛋白水平低,OP新生大鼠多巴胺细胞培养。建议的干预措施,以改变OP表型和相关的中枢多巴胺神经传递,包括放置OP窝与OR母鼠在第一天PO,VMAT 2过表达的OP大鼠,和OP和OR大鼠的配对喂养。

项目成果

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Brenda Geiger其他文献

Brenda Geiger的其他文献

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{{ truncateString('Brenda Geiger', 18)}}的其他基金

CNS Dopamine as Marker for Obesity Predisposition: Link to Food and Drug Reward
中枢神经系统多巴胺作为肥胖倾向的标志:与食品和药物奖励的联系
  • 批准号:
    7333499
  • 财政年份:
    2007
  • 资助金额:
    $ 3.26万
  • 项目类别:
CNS Dopamine as Marker for Obesity Predisposition: Link to Food and Drug Reward
中枢神经系统多巴胺作为肥胖倾向的标志:与食品和药物奖励的联系
  • 批准号:
    7684058
  • 财政年份:
    2007
  • 资助金额:
    $ 3.26万
  • 项目类别:
CNS Dopamine as Marker for Obesity Predisposition: Link to Food and Drug Reward
中枢神经系统多巴胺作为肥胖倾向的标志:与食品和药物奖励的联系
  • 批准号:
    7501298
  • 财政年份:
    2007
  • 资助金额:
    $ 3.26万
  • 项目类别:

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