The 5-HT2C Receptor Agonist Lorcaserin Reduces Nicotine Self-Administration, Discrimination, and Reinstatement: Relationship to Feeding Behavior and Impulse Control
The 5-HT2C Receptor Agonist Lorcaserin Reduces Nicotine Self-Administration, Discrimination, and Reinstatement: Relationship to Feeding Behavior and Impulse Control
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DOI：
10.1038/npp.2011.303
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发表时间：
2012-04-01
影响因子：
7.6
通讯作者：
Fletcher, Paul J.
中科院分区：
文献类型：
--
作者：
Higgins, Guy A.;Silenieks, Leo B.;Fletcher, Paul J.
氯卡色林（（1 R）-8-氯-1-甲基-2，3，4，5-四氢-1H-3-苯并氮杂卓盐酸盐）是一种选择性5-HT 2C受体激动剂，在III期肥胖试验中具有临床疗效。基于这类药物也影响药物强化行为的证据，我们比较了氯卡色林对食物和尼古丁强化行为的影响，以及尼古丁在大鼠中的刺激和辨别刺激特性。急性给药氯卡色林（0.3-3 mg/kg，皮下（SC））剂量依赖性地减少了22小时禁食诱导的摄食或适口性。高达1 mg/kg的影响与对摄食动机的特定影响一致。氯卡色林（0.6-1 mg/kg，SC）降低了渐进和固定比例强化方案下对食物的操作性反应。在该剂量范围内，氯卡色林还逆转了尼古丁的运动刺激作用，减少了尼古丁的静脉自我给药，并减弱了训练区分尼古丁和生理盐水的大鼠中的尼古丁线索。氯卡色林还减少了由复合线索引起的尼古丁寻求行为的恢复，该复合线索包括尼古丁引发和先前与尼古丁强化配对的条件刺激。氯卡色林不能恢复尼古丁寻求行为或替代尼古丁线索。最后，氯卡色林（0.3-1 mg/kg）减少了尼古丁诱导的预期反应增加，这是一种冲动行为的测量方法，在大鼠中执行五种选择系列反应时间任务。重要的是，这些结果表明，氯卡色林和其他可能的选择性5-HT 2C受体激动剂，同样影响食物和尼古丁动机的行为，以及尼古丁诱导的冲动。总的来说，这些发现突出了5-HT 2C激动剂如氯卡色林的治疗潜力，超越了肥胖到成瘾行为，如尼古丁依赖。Neuropsychopharmacology（2012）37，1177-1191; doi：10.1038/npp.2011.303; 2011年12月21日在线发表
Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT2C receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT2C receptor agonists, similarly affect both food-and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT2C agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence. Neuropsychopharmacology (2012) 37, 1177-1191; doi:10.1038/npp.2011.303; published online 21 December 2011