Endogenous opioids, and in particular μ-opioid receptors, have been linked to hedonic and rewarding mechanisms engaged during palatable food intake. The aim of this study was to investigate the effects of GSK1521498, a novel μ-opioid receptor antagonist, on food-seeking behavior and on binge-like eating of a highly preferred chocolate diet. Food seeking was measured in rats trained to respond for chocolate under a second-order schedule of reinforcement, in which prolonged periods of food-seeking behavior were maintained by contingent presentation of a reward-associated conditioned reinforcer. After reaching a stable baseline in both procedures, animals were treated with GSK1521498 (0.1, 1, and 3 mg/kg; IP) or naltrexone (NTX, 0.1, 1, and 3 mg/kg; SC). The binge eating model was characterized by four temporally contiguous phases: 1-h chow access, 2-h food deprivation, 10-min chow access, and 10-min access to either chocolate-flavoured food or standard chow. During training the rats developed binge-like hyperphagia of palatable food and anticipatory chow hypophagia (anticipatory negative contrast). Both compounds reduced binge-like palatable food hyperphagia. However, GSK1521498 reduced the impact of high hedonic value on ingestion more specifically than NTX, abolishing anticipatory chow hypophagia. GSK1521498 also dose-dependently reduced food seeking both before and after food ingestion, whereas NTX reduced food seeking only after food ingestion. Thus, while both drugs affected the hedonic value of the preferred food, GSK1521498 also directly decreased incentive motivation for chocolate. Selective μ-opioid receptor antagonism by GSK1521498 may have utility as a treatment for reducing maladaptive, palatability-driven eating behavior by reducing the motivational properties of stimuli that elicit the binge eating commonly associated with obesity.

译文

:内源性阿片类药物,尤其是μ阿片类药物受体,已与可口食物摄入中所享享的享乐和奖励机制有关。这项研究的目的是研究一种新型的μ阿片受体拮抗剂GSK1521498对寻求食物的行为以及暴饮暴食的巧克力饮食的影响。在训练后对巧克力有反应的大鼠中测量食物的觅食能力,其中通过与奖励相关的条件增强剂的偶然性表现来维持长时间的食物寻找行为。在两种方法中均达到稳定的基线后,用GSK1521498(0.1、1和3μmg/ kg; IP)或纳曲酮(NTX,0.1、1和3μmg/ kg; SC)治疗动物。暴饮暴食模型的特征在于四个时间上连续的阶段:1-h饮食,2-h食物匮乏,10分钟的饮食和10分钟的巧克力味食品或标准食物。在训练过程中,大鼠出现了可口食物的暴食状食欲过大和预期的食物不足(预期的负对比)。两种化合物均减少了暴食样可食性食物过多症。但是,GSK1521498比NTX更能降低高享乐值对摄入的影响,从而消除了预期食物的吞咽不足。 GSK1521498还可以在食物摄取之前和之后剂量依赖性地减少食物摄取,而NTX仅在食物摄取之后减少食物摄取。因此,尽管两种药物都影响首选食品的享乐价值,但GSK1521498也直接降低了巧克力的诱因。 GSK1521498的选择性μ阿片类药物受体拮抗作用可通过减少引起肥胖症的暴食饮食的动机来减少不良适应性,适口性驱动的饮食行为。

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