• Neil E Paterson, Wenzhong Min, Adrian Hackett, David Lowe, Taleen Hanania, Barbara Caldarone, and Afshin Ghavami.
• PsychoGenics, Inc., 765 Old Saw Mill River Rd., Tarrytown, NY 10591, United States. Neil.Paterson@PsychoGenics.com
• Prog. Neuropsychopharmacol. Biol. Psychiatry. 2010 Dec 1; 34 (8): 1455-64.

AbstractVarenicline (Chantix®, Champix®) 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 α4β2* 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 μg/kg/inf, respectively) or progressive-ratio (peak responding at 30-60, 30-100 and 30 μg/kg/inf, respectively) schedules in rats trained to self-administer nicotine. Varenicline (ED(50) 0.2 mg/kg) and sazetidine-A (ED(50) 0.44 mg/kg) fully substituted for nicotine (ED(50) 0.09 mg/kg) in rats trained to discriminate nicotine (0.4 mg/kg, i.p.) 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 α4* nAChR-selective antagonist dihydro-β-erythroidine, but not by the α7 nAChR subtype antagonist methyllycaconitine. Drug-naïve rats acquired stable self-administration of varenicline (30 μg/kg/inf), and sazetidine-A (60 μg/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 α4β2* 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-naïve rats. Future studies should assess nicotine withdrawal measures in animals chronically exposed to varenicline or sazetidine-A.Copyright © 2010 Elsevier Inc. All rights reserved.

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