Paterson_2010_Prog.Neuropsychopharmacol.Biol.Psychiatry_34_1455

Reference

Title : The high-affinity nAChR partial agonists varenicline and sazetidine-A exhibit reinforcing properties in rats - Paterson_2010_Prog.Neuropsychopharmacol.Biol.Psychiatry_34_1455
Author(s) : Paterson NE , Min W , Hackett A , Lowe D , Hanania T , Caldarone B , Ghavami A
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 34 :1455 , 2010
Abstract :

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 alpha4beta2* 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 mug/kg/inf, respectively) or progressive-ratio (peak responding at 30-60, 30-100 and 30 mug/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 alpha4* nAChR-selective antagonist dihydro-beta-erythroidine, but not by the alpha7 nAChR subtype antagonist methyllycaconitine. Drug-naive rats acquired stable self-administration of varenicline (30 mug/kg/inf), and sazetidine-A (60 mug/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 alpha4beta2* 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.

PubMedSearch : Paterson_2010_Prog.Neuropsychopharmacol.Biol.Psychiatry_34_1455
PubMedID: 20708056

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Citations formats

Paterson NE, Min W, Hackett A, Lowe D, Hanania T, Caldarone B, Ghavami A (2010)
The high-affinity nAChR partial agonists varenicline and sazetidine-A exhibit reinforcing properties in rats
Prog Neuropsychopharmacol Biological Psychiatry 34 :1455

Paterson NE, Min W, Hackett A, Lowe D, Hanania T, Caldarone B, Ghavami A (2010)
Prog Neuropsychopharmacol Biological Psychiatry 34 :1455