Loss of sensitivity to varenicline in monkeys receiving chronic nicotine treatment.

Given the adverse health consequences of tobacco use, there is a need to understand pharmacologic mechanisms of drug action as a function of nicotine treatment. Here, the effects of nicotine and varenicline (Chantix) were compared under two distinct conditions of nicotine treatment. One group (n=5) of rhesus monkeys discriminated nicotine base (1.78 mg/kg) from saline; the same dose of nicotine was discriminated by a second group of monkeys that received 8.9–10.68 mg/kg/day. Nicotine dose‐dependently increased nicotine‐lever responding in both groups; the ED50 value without daily nicotine treatment (0.47 mg/kg) was not different from that with daily nicotine treatment (0.30 mg/kg). In contrast, varenicline produced 98% nicotine‐lever responding in monkeys not receiving nicotine daily (ED50 value = 0.53 mg/kg), but only produced a maximum of 10% nicotine‐lever responding in monkeys receiving nicotine daily. Although a loss in the discrimination of varenicline in monkeys receiving large doses of nicotine daily is consistent with varenicline having lower agonist efficacy than nicotine, their combined effects did not confirm this possibility inasmuch as varenicline did not shift the nicotine dose‐effect function rightward. A difference in agonist efficacy at a common receptor type is not sufficient to account for the striking loss of sensitivity to varenicline resulting from nicotine treatment.