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

Kathleen R. McNealy; MacKenzie L. Knabel; Scott T. Barrett; Cassandra D. Gipson; Tierney K. Lorenz; Rick A. Bevins

doi:10.1016/j.neuropharm.2025.110681

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

Kathleen R. McNealy
, MacKenzie L. Knabel
, Scott T. Barrett
, Cassandra D. Gipson
, Tierney K. Lorenz
, Rick A. Bevins

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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.

Original language	English
Article number	110681
Journal	Neuropharmacology
Volume	280
DOIs	https://doi.org/10.1016/j.neuropharm.2025.110681
State	Published - Dec 1 2025

Bibliographical note

Publisher Copyright:
© 2025

Funding

Notably, prior research supports that EE-containing hormonal contraceptive formulations are associated with heightened smoking satisfaction and smoking reward relative to naturally cycling women (Hinderaker et al., 2015), and that EE increases self-administration of 0.06 mg/kg/inf nicotine (with a VS) in ovariectomized rats (Maher et al., 2021). Several methodological differences may contribute to discrepancies between exacerbating effects of EE observed in Maher and colleagues (2021) and attenuating effects of EE observed in our Experiment 1. Among these include different rat strains (Long Evans versus our Sprague-Dawley), schedules of reinforcement (FR1 versus our VR3 and PR), and light cycle phase during self-administration (dark period versus our light period). Further, Maher and colleagues (2021) also implemented a single EE dose that was higher than either of our doses (0.3 μg/day). Of course, our use of ovary-intact rats versus their use of ovariectomized rats is perhaps the most important methodological difference. EE likely produces divergent effects when acting among endogenous hormonal milieu than in an ovariectomized rat that does not produce ovarian hormones. Indeed, as reported in the Supplementary materials, there was evidence of EE action on rat's endogenous progesterone production (although see below for notes on interpretation of these effects, section 5.2). Examining EE effects on nicotine self-administration in ovary-intact versus ovariectomized rats under identical experimental conditions is thus an important area of future research.We thank Matthew Oevermann, Sydney Houser, Ella Brester, Drake Reinke, Melisa Kulak, Killian Dwinell, Chase Auman, and Sophia Smyth for assisting in data collection on these projects. This research and all authors except for CGR and TKL were supported by National Institutes of Health (NIH) DA046109. This research and KRM were also supported by NIH DA059867. RAB was also partially supported by NIH GM130461. CGR was supported by NIH DA055879, DA046526, and DA061626. TKL was supported by NIH P20GM130461 and U54GM115458. MedPC programs are available in the dissertation of KRM, online in ProQuest. The ideas shared within this manuscript do not reflect the opinions of the University of Nebraska or the National Institute of Health. We thank Matthew Oevermann, Sydney Houser, Ella Brester, Drake Reinke, Melisa Kulak, Killian Dwinell, Chase Auman, and Sophia Smyth for assisting in data collection on these projects. This research and all authors except for CGR and TKL were supported by National Institutes of Health (NIH) DA046109. This research and KRM were also supported by NIH DA059867. RAB was also partially supported by NIH GM130461. CGR was supported by NIH DA055879, DA046526, and DA061626. TKL was supported by NIH P20GM130461 and U54GM115458. MedPC programs are available in the dissertation of KRM, online in ProQuest. The ideas shared within this manuscript do not reflect the opinions of the University of Nebraska or the National Institute of Health.

Funders	Funder number
light cycle phase
University of Nebraska–Lincoln
National Institutes of Health (NIH)	DA061626, DA059867, DA055879, DA046109, DA046526, U54GM115458, P20GM130461

Keywords

Cues
Primary reinforcement
Smoking
Synthetic hormones
Vaping
Women

ASJC Scopus subject areas

Pharmacology
Cellular and Molecular Neuroscience

Access to Document

10.1016/j.neuropharm.2025.110681

Cite this

McNealy, K. R., Knabel, M. L., Barrett, S. T., Gipson, C. D., Lorenz, T. K., & Bevins, R. A. (2025). Contraceptive hormone ethinyl estradiol but not levonorgestrel modulates the role of reinforcer-enhancement in nicotine self-administration in ovary-intact female Sprague-Dawley rats. Neuropharmacology, 280, Article 110681. https://doi.org/10.1016/j.neuropharm.2025.110681

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

abstract = "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.",

keywords = "Cues, Primary reinforcement, Smoking, Synthetic hormones, Vaping, Women",

author = "McNealy, \{Kathleen R.\} and Knabel, \{MacKenzie L.\} and Barrett, \{Scott T.\} and Gipson, \{Cassandra D.\} and Lorenz, \{Tierney K.\} and Bevins, \{Rick A.\}",

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doi = "10.1016/j.neuropharm.2025.110681",

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Contraceptive hormone ethinyl estradiol but not levonorgestrel modulates the role of reinforcer-enhancement in nicotine self-administration in ovary-intact female Sprague-Dawley rats. / McNealy, Kathleen R.; Knabel, MacKenzie L.; Barrett, Scott T. et al.
In: Neuropharmacology, Vol. 280, 110681, 01.12.2025.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Contraceptive hormone ethinyl estradiol but not levonorgestrel modulates the role of reinforcer-enhancement in nicotine self-administration in ovary-intact female Sprague-Dawley rats

AU - McNealy, Kathleen R.

AU - Knabel, MacKenzie L.

AU - Barrett, Scott T.

AU - Gipson, Cassandra D.

AU - Lorenz, Tierney K.

AU - Bevins, Rick A.

PY - 2025/12/1

Y1 - 2025/12/1

N2 - 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.

AB - 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.

KW - Cues

KW - Primary reinforcement

KW - Smoking

KW - Synthetic hormones

KW - Vaping

KW - Women

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ER -

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

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

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ASJC Scopus subject areas

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