Bupropion–varenicline interactions and nicotine self-administration behavior in rats

Abstract

Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose–effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague–Dawley rats were allowed to self-administer nicotine in 1-h sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3mg/kg) and bupropion (8.33, 25, 75mg/kg) were administered alone or together 15min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3mg/kg varenicline and 75mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3mg/kg varenicline dose combined with the 25 and 75mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combining 1mg/kg varenicline with 75mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone.