Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Pharmacol Biochem Behav. 2013 Nov;112:1-8. doi: 10.1016/j.pbb.2013.09.003. Epub 2013 Sep 21.
Serotonin acts through receptors controlling several physiological functions, including energy homeostasis regulation and food intake. Recent experiments demonstrated that 5-HT1A receptor antagonists reduce food intake. We sought to examine the microstructure of feeding with 5-HT1A receptor antagonists using a food intake monitoring system. We also examined the relationship between food intake, inhibition of binding and pharmacokinetic (PK) profiles of the antagonists. Ex vivo binding revealed that, at doses used in this study to reduce food intake, inhibition of binding of a 5-HT1A agonist by ~40% was reached in diet-induced obese (DIO) mice with a trend for higher binding in DIO vs. lean animals. Additionally, PK analysis detected levels from 2 to 24h post-compound administration. Male DIO mice were administered 5-HT1A receptor antagonists LY439934 (10 or 30 mg/kg, p.o.), WAY100635 (3 or 10mg/kg, s.c.), SRA-333 (10 or 30 mg/kg, p.o.), or NAD-299 (3 or 10mg/kg, s.c.) for 3 days and meal patterns were measured. Analyses revealed that for each antagonist, 24-h food intake was reduced through a specific decrease in the total number of meals. Compared to controls, meal number was decreased 14-35% in the high dose. Average meal size was not changed by any of the compounds. The reduction in food intake reduced body weight 1-4% compared to Vehicle controls. Subsequently, a conditioned taste aversion (CTA) assay was used to determine whether the feeding decrease might be an indicator of aversion, nausea, or visceral illness caused by the antagonists. Using a two bottle preference test, it was found that none of the compounds produced a CTA. The decrease in food intake does not appear to be a response to nausea or malaise. These results indicate that 5-HT1A receptor antagonist suppresses feeding, specifically by decreasing the number of meals, and induce weight loss without an aversive side effect.
血清素通过控制多种生理功能的受体发挥作用，包括能量平衡调节和食物摄入。最近的实验表明，5-HT1A 受体拮抗剂可减少食物摄入。我们试图使用食物摄入监测系统检查 5-HT1A 受体拮抗剂对进食的微观结构的影响。我们还检查了食物摄入、结合抑制和拮抗剂的药代动力学（PK）特征之间的关系。离体结合显示，在本研究中用于减少食物摄入的剂量下，在饮食诱导肥胖（DIO）小鼠中，5-HT1A 激动剂的结合抑制达到约 40%，并且 DIO 动物的结合趋势更高。此外，PK 分析检测到化合物给药后 2 至 24 小时的水平。雄性 DIO 小鼠给予 5-HT1A 受体拮抗剂 LY439934（10 或 30mg/kg，po），WAY100635（3 或 10mg/kg，sc），SRA-333（10 或 30mg/kg，po）或 NAD-299（3 或 10mg/kg，sc）连续 3 天，并测量进餐模式。分析表明，对于每种拮抗剂，通过总进餐次数的特定减少来减少 24 小时食物摄入。与对照组相比，高剂量时的进餐次数减少了 14-35%。平均进餐量未被任何化合物改变。与载体对照组相比，食物摄入量的减少导致体重减轻 1-4%。随后，使用条件性味觉厌恶（CTA）测定来确定摄食减少是否可能是拮抗剂引起的厌恶、恶心或内脏疾病的指标。使用两瓶偏好测试，发现没有一种化合物产生 CTA。食物摄入量的减少似乎不是对恶心或不适的反应。这些结果表明，5-HT1A 受体拮抗剂通过减少进餐次数来抑制进食，并在没有厌恶副作用的情况下诱导体重减轻。
