Attenuated nicotine-like effects of varenicline but not other nAChR agonists in monkeys receiving nicotine daily
Background and Purpose Chronic treatment can differentially impact the effects of pharmacologically related drugs that differ in receptor selectivity and efficacy. Experimental Approach The impact of daily nicotine treatment on the effects of nAChR agonists was examined in two groups of rhesus monkeys discriminating nicotine (1.78 mg•kg-1 base weight) from saline. One group received additional nicotine treatment post-session (1.78 mg•kg-1 administered 5 times daily, each dose 2 h apart; i.e., Daily group) and the second group did not (i.e., Intermittent group). Key Results Daily nicotine yielded 5,128 and 15,320 ng of cotinine per ml saliva before the first and last daily dose, respectively. The ED50 values of the nicotine discriminative stimulus were 0.67 mg•kg-1 in the Daily group and 0.40 mg•kg-1 in the Intermittent group. Mecamylamine (1 mg•kg-1) antagonized nicotine, whereas dihydro-β-erythroidine (3.2 mg•kg-1) did not. Midazolam produced 0% nicotine-lever responding. The nAChR agonists epibatidine, RTI-36, cytisine, and varenicline produced >96% nicotine-lever responding in the Intermittent group. The respective maximum effects in the Daily group were 100%, 72%, 59%, and 28%. The potency of varenicline was selectively decreased in the Daily as compared with the Intermittent group. When combined with nicotine, both varenicline (3.2 mg•kg-1) and cytisine (32 mg•kg-1) increased the potency of nicotine to produce discriminative stimulus effects. Conclusion and Implications Nicotine treatment has greater impact on sensitivity to the effects of varenicline as compared with some other nAChR agonists. Collectively, these results strongly suggest that varenicline differs from nicotine in selectivity for multiple nAChR subtypes.