R S Mansbach1, L K Chambers, C C Rovetti. 1. Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA. mansbachrs@groton.pfizer.com
Abstract
RATIONALE: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed beta32-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine's acute subjective and reinforcing effects. OBJECTIVE: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. METHODS: Adult male rats were trained to discriminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. RESULTS: Erysodine (0.3-10 mg/kg) and mecamylamine (0.1-1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32-32 mg/kg) and mecamylamine (0.32-3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. CONCLUSIONS: Based on the known affinity of erysodine for alpha4beta2 nACHRs and its selectivity relative to alpha7 and alpha1beta1gammadelta receptors, the present data support a critical role of beta2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
RATIONALE: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed beta32-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine's acute subjective and reinforcing effects. OBJECTIVE: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. METHODS: Adult male rats were trained to discriminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. RESULTS:Erysodine (0.3-10 mg/kg) and mecamylamine (0.1-1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32-32 mg/kg) and mecamylamine (0.32-3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. CONCLUSIONS: Based on the known affinity of erysodine for alpha4beta2 nACHRs and its selectivity relative to alpha7 and alpha1beta1gammadelta receptors, the present data support a critical role of beta2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
Authors: Matthew I Palmatier; Xiu Liu; Anthony R Caggiula; Eric C Donny; Alan F Sved Journal: Neuropsychopharmacology Date: 2006-11-08 Impact factor: 7.853
Authors: Xiu Liu; Anthony R Caggiula; Susan K Yee; Hiroko Nobuta; Alan F Sved; Robert N Pechnick; Russell E Poland Journal: Neuropsychopharmacology Date: 2006-06-21 Impact factor: 7.853
Authors: Emily M Jutkiewicz; Emily A Brooks; Adam D Kynaston; Kenner C Rice; James H Woods Journal: J Pharmacol Exp Ther Date: 2011-07-05 Impact factor: 4.030