title: The high-affinity nAChR partial agonists varenicline and sazetidine-A exhibit reinforcing properties in rats.
abstract: Varenicline (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.
authors: PsychoGenics, Inc., 765 Old Saw Mill River Rd., Tarrytown, NY 10591, United States. Neil.Paterson@PsychoGenics.com
authors: Neil E
authors: NE
authors: Paterson
authors: Wenzhong
authors: W
authors: Min
authors: Adrian
authors: A
authors: Hackett
authors: David
authors: D
authors: Lowe
authors: Taleen
authors: T
authors: Hanania
authors: Barbara
authors: B
authors: Caldarone
authors: Afshin
authors: A
authors: Ghavami
mesh_terms: D000818:Animals; D001384:Azetidines / Q000008:administration & dosage* / Q000378:metabolism; D001552:Benzazepines / Q000008:administration & dosage* / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D054333:Drug Partial Agonism; D008297:Male; D018722:Nicotinic Agonists / Q000008:administration & dosage* / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage* / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration; D000068580:Varenicline
chemical_list: D001384:Azetidines; D001552:Benzazepines; D018722:Nicotinic Agonists; D011725:Pyridines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C514816:sazetidine-A; D000068580:Varenicline