Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement

• Published in: Neuropharmacology Vol. 62; no. 7; pp. 2287 - 2297
• Main Authors: Fletcher, Paul J., Rizos, Zoë, Noble, Kevin, Soko, Ashlie D., Silenieks, Leo B., Lê, Anh Dzung, Higgins, Guy A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2012
• Subjects: 5-HT2A; 5-HT2C; Animals; Brain; Dopamine; Drug dependence; Drug self-administration; Drugs; Ethylamines - pharmacology; Fluorobenzenes - pharmacology; Food; Indoles - pharmacology; Light effects; Male; Nicotine; Nicotine - administration & dosage; Piperidines - pharmacology; Rats; Rats, Long-Evans; Reaction Time - drug effects; Reaction Time - physiology; Receptor mechanisms; Reinforcement; Reinstatement; Self Administration; Serotonin; Serotonin 5-HT2 Receptor Agonists - pharmacology; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Serotonin S2 receptors; Self-administration; 5-HT2C; Serotonin; Reinstatement; Nicotine; 5-HT2A
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.01.023

The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT2A and 5-HT2C receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 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 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-HT2C receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT2C and 5-HT2A receptors may be potential targets for therapies to treat some aspects of nicotine dependence.
► The 5-HT2C receptor agonist Ro60-0175 reduced nicotine self-administration. ► Ro60-0175 reduced reinstatement of nicotine-seeking elicited by nicotine, or nicotine cues. ► All effects of Ro60-0175 were reversed by a 5-HT2C receptor antagonist. ► The 5-HT2A receptor antagonist M100907 did not affect nicotine self-administration. ► M100907 attenuated reinstatement of nicotine-seeking.