The high-affinity nAChR partial agonists varenicline and sazetidine-A exhibit reinforcing properties in rats

Varenicline (Chantix (R), Champix (R)) is a nicotinic acetylcholine receptor (nAChR) partial agonist clinically approved for smoking cessation, yet its potential abuse liability properties have not been fully characterized. The nAChR ligand sazetidine-A has been reported as a selective full or partial agonist at alpha 4 beta 2* nAChR subtypes in in vitro studies. In the present studies, varenicline, sazetidine-A and nicotine exhibited inverted U-shaped dose-response functions under fixed-ratio (peak responding at 30, 60 and 10-30 mu g/kg/inf, respectively) or progressive-ratio (peak responding at 30-60, 30-100 and 30 mu g/kg/inf, respectively) schedules in rats trained to self-administer nicotine. Varenicline (ED50 0.2 mg/kg) and sazetidine-A (ED50 0.44 mg/kg) fully substituted for nicotine (ED50 0.09 mg/kg) in rats trained to discriminate nicotine (0.4 mg/kg, ip) from saline. The reinforcing and discriminative stimulus (DS) properties of sazetidine-A, varenicline and nicotine were attenuated by acute pretreatment with the non-selective neuronal non-competitive nAChR antagonist mecamylamine or the alpha 4* nAChR-selective antagonist dihydro-beta-erythroidine, but not by the alpha 7 nAChR subtype antagonist methyllycaconitine. Drug-naive rats acquired stable self-administration of varenicline (30 mu g/kg/inf.), and sazetidine-A (60 mu g/kg/inf), at doses that supported peak responding under a fixed-ratio 3 schedule in nicotine-trained rats. Nonetheless, self-administration and re-acquisition of varenicline and sazetidine-A were less robust than nicotine. Thus, partial activation of alpha 4 beta 2* nAChRs by varenicline or sazetidine-A is sufficient to mimic the DS and reinforcing properties of nicotine in nicotine-experienced rats, although the reinforcing properties of partial agonists are diminished in nicotine-naive rats. Future studies should assess nicotine withdrawal measures in animals chronically exposed to varenicline or sazetidine-A. (C) 2010 Elsevier Inc. All rights reserved.