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Enhancement and perceptual masking of a nicotine discriminative stimulus in rhesus monkeys

Bupropion and varenicline are two pharmacotherapies (Zyban® and Chantix®, respectively) for smoking cessation. Bupropion is a monoamine reuptake inhibitor that is also a nicotinic antagonist. Varenicline has lower efficacy than nicotine at α4β2 nicotinic receptors in vitro, and is expected to antagonize the effects of nicotine. The extent to which these drugs interact with nicotine has not been fully established. To examine the ability of nicotinic as well as non‐nicotinic compounds (cocaine and midazolam) to alter the discriminative stimulus effects of nicotine, 5 adult rhesus monkeys were trained to discriminate nicotine (1.78 mg/kg base) under a fixed ratio 5 schedule. Bupropion produced 23% nicotine lever responding and antagonized the nicotine discriminative stimulus, as evidenced by a rightward shift in the nicotine dose‐response curve. Varenicline fully substituted for nicotine and the combined effects of nicotine and varenicline were synergistic. The monoamine reuptake blocker cocaine and the benzodiazepine midazolam produced nicotine lever responding when given alone (44% and 4%, respectively) and antagonized the nicotine discriminative stimulus. Varenicline produced synergistic effects with nicotine, inconsistent with low efficacy at a common site in vivo. Antagonism of the nicotine discriminative stimulus by bupropion, cocaine, and midazolam is consistent with perceptual masking.