The effects of nicotine, varenicline, and cytisine on schedule-controlled responding in mice: differences in α4β2 nicotinic receptor activation.

Nicotine, varenicline, and cytisine are pharmacotherapies for tobacco dependence; the extent to which their in vivo effects vary as a function of differences in nicotinic acetylcholine receptor agonism is not clear. Male C57BL/6J mice responding under a fixed ratio 30 schedule of food delivery were used to establish the potency and time course of nicotine, varenicline, and cytisine; antagonism was examined with the non-competitive, non-selective antagonist mecamylamine and the competitive, α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE). Intraperitoneal nicotine, varenicline, and cytisine dose-dependently decreased responding; nicotine was more potent (ED(50) value=0.83 mg/kg) than varenicline (ED(50) value=2.51 mg/kg) and cytisine (ED(50) value=2.97 mg/kg). The agonists had a similar time course including a rapid onset (5 min or less) and relatively short duration of action (30 min). Mecamylamine dose-dependently attenuated the rate-decreasing effects of a fixed dose of nicotine (1.78 mg/kg), varenicline (5.6 mg/kg), and cytisine (5.6 mg/kg). Mecamylamine (1mg/kg) produced parallel rightward shifts in the dose-response curves for nicotine (3.3-fold), varenicline (3.1-fold), and cytisine (2.3-fold). In contrast, DHβE (3.2mg/kg) produced 2-fold antagonism of nicotine and did not antagonize varenicline or cytisine. The data strongly suggest that nicotinic acetylcholine receptors mediate the effects of the agonists to decrease operant responding in mice. However, α4β2 receptor agonism appears to contribute partially to the rate-decreasing effects of nicotine but not to the rate-decreasing effects of varenicline and cytisine. Differential activation of α4β2 receptors in vivo might contribute to differences in the effectiveness of these smoking cessation aids.

Cunningham CS ，McMahon LR 《-》

Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids.

Cunningham CS ，McMahon LR 《-》

The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice.

de Moura FB ，McMahon LR 《-》

Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys.

Cunningham CS ，Javors MA ，McMahon LR 《-》

Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: scheduled-controlled responding and hypothermia in C57BL/6J mice.

de Moura FB ，McMahon LR 《-》