The 5-HT2C Receptor Agonist Lorcaserin Reduces Nicotine Self-Administration, Discrimination, and Reinstatement: Relationship to Feeding Behavior and Impulse Control

被引:110
作者
Higgins, Guy A. [1 ,2 ]
Silenieks, Leo B. [1 ]
Rossmann, Anne [1 ]
Rizos, Zoe [3 ]
Noble, Kevin [3 ]
Soko, Ashlie D. [3 ]
Fletcher, Paul J. [3 ,4 ]
机构
[1] InterVivo Solut Inc, Toronto, ON M5A 4K2, Canada
[2] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada
[3] Ctr Addict & Mental Hlth, Sect Biopsychol, Clarke Div, Toronto, ON, Canada
[4] Univ Toronto, Dept Psychiat & Psychol, Toronto, ON, Canada
基金
加拿大健康研究院;
关键词
reward; obesity; nicotine dependence; impulsivity; addiction; 5-HT2C receptor; REACTION-TIME-TASK; LOCOMOTOR-ACTIVITY; D-FENFLURAMINE; SEROTONERGIC DRUGS; SMOKING-CESSATION; SATIETY SEQUENCE; ACTIVATION; COCAINE; PHARMACOLOGY; STIMULATION;
D O I
10.1038/npp.2011.303
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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
引用
收藏
页码:1177 / 1191
页数:15
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