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.