Involvement of nicotinic receptor subtypes in the behavioral effects of nicotinic drugs in squirrel monkeys

Abstract

Evidence suggests that the a4b2, but not the a7, subtype of the nicotinic acetylcholine receptor (nAChR) plays a key role in mediating the behavioral effects of nicotine and related drugs. However, the importance of other nAChR subtypes remains unclear. The present studies were conducted to examine the involvement of nAChR subtypes by determining the effects of selected nicotinic agonists and antagonists in squirrel monkeys either 1) responding for food reinforcement or 2) discriminating the nicotinic agonist (1)-epibatidine (0.001 mg/kg) from vehicle. In food-reinforcement studies, nicotine, (1)-epibatidine, varenicline and cytisine all produced dose-dependent decreases in rates of food-maintained responding. The rate-decreasing effects of nicotine were antagonized by mecamylamine (nonselective), not appreciably altered by dihydro-b-erythroidine (a4b2 selective), and exacerbated by the nicotinic partial agonists, varenicline and cytisine. Results from discrimination studies show that non-nicotinic drugs did not substitute for (1)-epibatidine, and that except for lobeline, the nicotinic agonists produced either full [(1)-epibatidine, (2)-epibatidine, and nicotine] or partial (varenicline, cytisine, anabaseine, and isoarecolone) substitution for (1)-epibatidine. In interaction studies with antagonists differing in selectivity, (1)-epibatidine discrimination was substantively antagonized by mecamylamine, slightly attenuated by hexamethonium (peripherally restricted) or dihydro-b-erythroidine, and not altered by methyllycaconitine (a7 selective). Varenicline and cytisine enhanced (1)-epibati-dine’s discriminative-stimulus effects. Correlational analysis revealed a close correspondence between relative behavioral potencies of nicotinic agonists in both studies and their published relative binding affinities at a4b2 and a3b4, but not a7 nAChR, subtypes. Collectively, these results are consistent with the idea that the a4b2 and a3b4, but not a7 nAChR subtypes play a role in the behavioral effects of nicotinic agonists.