Effects of the 5-HT_2C receptor agonist Ro60-0175 and the 5-HT_2A receptor antagonist M100907 on nicotine self-administration and reinstatement

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• 作者：Paul J. Fletcher^a ; ^b ; ^c ; ^{Paul_Fletcher@camh.net} ; Zo5 ; Rizos^a ; Kevin Noble^a ; Ashlie D. Soko^a ; Leo B. Silenieks^e ; Anh Dzung Lê ; ^a ; ^d ; Guy A. Higgins^d ; ^e
• 关键词：Nicotine ; Self-administration ; Reinstatement ; Serotonin ; 5-HT2A ; 5-HT2C
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：June, 2012
• 卷：62
• 期：7
• 页码：2288-2298
• 文件大小：586 K

摘要

The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT_2A and 5-HT_2C receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT_2C receptor agonist Ro60-0175 and the 5-HT_2A receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03聽mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement, response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15聽mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT_2C receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT_2C and 5-HT_2A receptors may be potential targets for therapies to treat some aspects of nicotine dependence.