Understanding the stimulus effects of nicotine and bupropion in a drug-drug discriminated goal-tracking task

Rationale: Bupropion is a non-nicotine medication for smoking cessation that has overlapping stimulus effects with nicotine as demonstrated in drug discrimination studies. Whether these shared stimulus effects will alter acquisition or maintenance of a discrimination between nicotine and bupropion is unknown. Objective: We sought to test this possibility using the drug discriminated goal-tracking (DGT) task and whether discrimination training history affected generalization and substitution tests. Methods: Sixty adult Sprague–Dawley rats (30M/30F) were equally split into three discrimination training groups: SAL–0.4NIC, 10BUP–0.4NIC, and 20BUP–0.4NIC. On nicotine days, all rats were administered subcutaneously 0.4 mg/kg nicotine and had intermittent access to liquid sucrose. On intermixed non-reinforced days, rats were administered intraperitoneally saline, 10 or 20 mg/kg bupropion. Upon completion, a range of nicotine and bupropion doses were assessed before substitution tests with varenicline and sazetidine-A were conducted. Results: The SAL–0.4NIC and 10BUP–0.4NIC groups readily discriminated by session 8, as evidenced by increased dipper entries (goal-tracking) on nicotine days. The 20BUP–0.4NIC group was slower to acquire the discrimination. Female rats, regardless of group, had higher conditioned responding evoked by the lowest dose of nicotine (0.025 mg/kg) in the dose–effect curve. The discrimination required rats to learn to withhold responding to the training dose of bupropion. This withholding of excitatory dipper entries generalized to other doses. Varenicline and sazetidine-A partially substituted for the nicotine stimulus, and this pattern did not differ with training history. Conclusions: We are the first to study a drug-drug discrimination using the DGT task. Females appeared to have a lower discrimination threshold for nicotine that was not impacted by the learning history. Further work on the importance of sex as a biological variable and how the complex interoceptive stimulus effects of nicotine can vary with training histories is needed.