Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles
Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles
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DOI：
10.1007/s00213-012-2919-2
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发表时间：
2013-04-01
影响因子：
3.4
通讯作者：
Fletcher, P. J.
中科院分区：
文献类型：
--
作者：
Higgins, G. A.;Silenieks, L. B.;Fletcher, P. J.
选择性 5-HT2C 受体激动剂（例如氯卡色林）正在开发用于治疗肥胖症。研究表明，它们还可能对包括尼古丁依赖在内的成瘾行为具有治疗潜力，尽管此类药物很少经过评估。主要目的是评估高选择性 5-HT2C 激动剂 CP-809101，对大鼠的食物驱动（操作 FR5 和渐进比例方案、适口性诱导喂养）和尼古丁驱动（静脉自我给药、药物歧视）行为，并与同等研究结果进行比较用于结构不同的 5-HT2C 受体激动剂 lorcaserin 和 Ro 60-0175。第二个目的是评估氯卡色林和 CP-809101 的副作用特征，并确定减少食物和尼古丁强化的剂量 (1 mg/kg) 的氯卡色林血浆水平，以便与人体试验中报告的血浆浓度进行比较。CP-809101 (0.3-3 mg/kg SC) 降低对尼古丁和食物的反应，并以与氯卡色林和 Ro 类似的方式阻断尼古丁的辨别刺激特性。 60-0175。在较高剂量的 CP-809101 和氯卡色林给药后，诸如运动不足、咀嚼和上睑下垂等行为变得明显。氯卡色林的血浆水平与肥胖试验中报告的范围相似。这些研究支持使用 5-HT2C 激动剂作为治疗尼古丁依赖的治疗方法。急性氯卡色林治疗后的血浆暴露水平表明，可以使用等效剂量在肥胖和戒烟试验中评估这些药物。最后，氯卡色林和 CP-809101 之间的副作用可能存在差异，从而增加了 5-HT2C 激动剂之间耐受性差异的可能性。
Selective 5-HT2C receptor agonists, such as lorcaserin, are being developed for the treatment of obesity. Studies suggest that they may also have therapeutic potential for addictive behaviours including nicotine dependence, although few drugs of this class have been evaluated.The primary aim was to evaluate the highly selective 5-HT2C agonist, CP-809101, against food-motivated (operant FR5 and progressive ratio schedules, palatability-induced feeding) and nicotine-motivated (intravenous self-administration, drug discrimination) behaviours in rats and to compare with equivalent findings for the structurally distinct 5-HT2C receptor agonists lorcaserin and Ro 60-0175. The secondary aims were to evaluate the side effect profiles of lorcaserin and CP-809101 and to determine the plasma levels of lorcaserin at a dose (1 mg/kg) that reduces both food and nicotine reinforcement for comparison to plasma concentrations reported in human trials.CP-809101 (0.3-3 mg/kg SC) reduced responding for both nicotine and food and blocked the discriminative stimulus properties of nicotine in a similar manner to lorcaserin and Ro 60-0175. Behaviours such as hypolocomotion, chewing and ptosis became evident following both CP-809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials.These studies support the utility of 5-HT2C agonists as a therapeutic approach to treat nicotine dependence. Plasma exposure levels after acute lorcaserin treatment suggest that equivalent dosages could be used to evaluate these drugs in obesity and smoking cessation trials. Finally, there may be differences in the side effect profiles between lorcaserin and CP-809101, raising the possibility for tolerability differences amongst 5-HT2C agonists.