Contraceptive hormone ethinyl estradiol but not levonorgestrel modulates the role of reinforcer-enhancement in nicotine self-administration in ovary-intact female Sprague-Dawley rats.

Hormonal contraceptives containing a synthetic estrogen (e.g., ethinyl estradiol/EE) and/or a progestin (e.g., levonorgestrel/LEVO) are associated with heightened nicotine use. Whether altered intake reflects changes in nicotine reinforcement or nicotine enhancement of co-occurring reinforcers is unknown. Reinforcer-enhancement is evidenced when nicotine self-administration increases when delivered with a reinforcing visual stimulus (VS). We examined EE and LEVO effects on nicotine reinforcement and reinforcer-enhancement in ovary-intact female Sprague-Dawley rats. Rats were implanted with a jugular catheter and received daily EE (Vehicle, 0.125 [Low], or 0.18 [High] μg/day; Experiment 1 N = 95) or LEVO (Vehicle, 0.3 [Low], or 0.6 [High] μg/day; Experiment 2 N = 113) injections. Rats responded for saline, 0.03 or 0.06 mg/kg/inf nicotine during two phases: the Infusion Only phase, responding only for their assigned solution, and the Infusion + VS phase, responding for their assigned solution and a VS. Each phase consisted of two Fixed Ratio-1 and ten Variable Ratio-3 sessions. The Infusion + VS phase included five additional Progressive Ratio sessions. In both experiments, only 0.06 mg/kg/inf nicotine maintained self-administration during the Infusion Only phase. This self-administration was unchanged by EE or LEVO. Nicotine self-administration increased during the Infusion + VS phase. In Experiment 1, 0.03 mg/kg/inf nicotine self-administration decreased with increasing EE dose; 0.06 mg/kg/inf nicotine self-administration was unchanged. For Experiment 2, LEVO did not alter self-administration. EE and LEVO were physiologically effective, evidenced by disrupted estrous cycling and EE increasing uterine weights. EE but not LEVO altered nicotine reinforcer-enhancement. These findings suggest a potential behavioral mechanism by which hormonal contraceptives alter nicotine intake in women.