title: Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement.
abstract: 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 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-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.
authors.affiliation: Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada. Paul_Fletcher@camh.net
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: Zoë
authors.initials: Z
authors.lastname: Rizos
authors.forename: Kevin
authors.initials: K
authors.lastname: Noble
authors.forename: Ashlie D
authors.initials: AD
authors.lastname: Soko
authors.forename: Leo B
authors.initials: LB
authors.lastname: Silenieks
authors.forename: Anh Dzung
authors.initials: AD
authors.lastname: Lê
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
mesh_terms: D000818:Animals; D005021:Ethylamines / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*
chemical_list: D005021:Ethylamines; D005464:Fluorobenzenes; D007211:Indoles; D010880:Piperidines; C103848:Ro 60-0175; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D009538:Nicotine; C079049:volinanserin