Effects of the competitive nicotinic antagonist erysodine on behavior occasioned or maintained by nicotine: comparison with mecamylamine

Rationale: The cellular effects of nicotine underlying its addictive liabil ity are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed beta 2-co ntaining nACHRs in the central nervous system are responsible for these act ions, but few data are available that can directly assess subtype mediation of nicotine's acute subjective and reinforcing effects. Objective: The pre sent study compared the effects of the competitive nACHR antagonist erysodi ne and the noncompetitive antagonist mecamylamine in rats trained to discri minate or self-administer nicotine, Methods: Adult male rats were trained t o disciminate 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 inj ections of nicotine under fixed-ratio 5 or progressive-ratio schedules of r einforcement. Additional rats were trained under a food-maintained procedur e of lever pressing. Results: Erysodine (0.3-10 mg/kg) and mecamylamine (0. 1-1.0 mg/kg) blocked nicotine discrimination, although only erysodine produ ced 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 selectiv ely reduced nicotine self-administration on a fixed-ratio schedule and lowe red break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for alpha 4 beta 2 nACHRs and its selectivity relative to alpha 7 and alpha 1 beta 1 gamma delta receptors, the present d ata support a critical role of beta 2-containing nACHR constructs in the di scriminative and reinforcing actions of nicotine.