Abstract
Rationale
Heroin intake decreases during the proestrus phase of the estrous cycle in female rats. Circulating concentrations of both estradiol and progesterone peak during proestrus, and it is not known which of these hormones, or their combination, are responsible for these effects.
Objectives
The purpose of this study was to determine the effects of estradiol, progesterone, and their combination on heroin self-administration in female rats.
Methods
In Experiment 1, the estrous cycle of intact female rats was tracked daily. If a rat was in proestrus, either the estrogen receptor antagonist, raloxifene, the progesterone receptor antagonist, mifepristone, or their combination was administered 30 min prior to a heroin self-administration session. In Experiment 2, separate groups of ovariectomized female rats were treated chronically with exogenous estradiol, progesterone, estradiol + progesterone, or vehicle, and heroin intake was examined over a 100-fold dose range.
Results
In Experiment 1, raloxifene, but not mifepristone, significantly blocked proestrus-associated decreases in heroin intake. In Experiment 2, estrogentreated rats self-administered less heroin than any other group and significantly less heroin than rats treated with progesterone.
Conclusions
These data suggest that (1) estradiol but not progesterone is responsible for proestrus-associated decreases in heroin intake and (2) estradiol decreases heroin intake relative to progesterone. These data differ from those reported previously with stimulants and suggest that estrogen-based pharmacotherapies may be of value to women with opioid use disorder.
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Acknowledgments
The authors thank the National Institute on Drug Abuse for supplying the study drug.
Funding
This work was supported by NIH Grants DA045364, DA031725, and DA045714. The NIH had no role in the writing of the manuscript or in the decision to submit the manuscript for publication.
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MAS developed the idea and wrote the manuscript. SBE, EP, HZ, MMM, SLB, ATC, KMP, and AMR were responsible for data collection and analysis. JLS and KTS provided intellectual contributions and edited the final manuscript. All authors approved the final manuscript.
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Smith, M.A., Ethridge, S.B., Pearson, T. et al. Modulation of heroin intake by ovarian hormones in gonadectomized and intact female rats. Psychopharmacology 238, 969–978 (2021). https://doi.org/10.1007/s00213-020-05743-1
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DOI: https://doi.org/10.1007/s00213-020-05743-1