Modulation of heroin intake by ovarian hormones in gonadectomized and intact female rats

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.

Keywords: Addiction; Estradiol; Opioid; Progesterone; Self-administration.

Figure 1.

Heroin intake in Experiment 1. All data reflect number of infusions over 2 hr. Panels 1a, 1c, and 1d depict heroin intake as a function of estrous phase in Experiments 1.1, 1.2, and 1.3, respectively. Panels 1b, 1d, and 1e depict heroin intake during proestrus as a function of mifepristone dose, raloxifene dose, or drug condition in Experiments 1.1, 1.2, and 1.3, respectively. Vertical bars represent the SEM (all panels). Asterisks indicate significant differences between phases of estrous (panels 1a, 1c, 1e) and between drug and vehicle conditions during proestrus (panels 1b, 1d, 1f).

Figure 2.

Heroin intake during the last five days of training in ovariectomized rats treated chronically with vehicle (VEH), progesterone (PRO), estradiol (EST), or progesterone + estradiol (P+E). Left panel depicts number of infusions over 2 hr as a function of training session. Right panel depicts total number of infusions over the five sessions. Vertical bars represent the SEM. Asterisk indicates significant difference between groups.

Figure 3.

Heroin intake during testing in ovariectomized rats treated chronically with vehicle (VEH), progesterone (PRO), estradiol (EST), or progesterone + estradiol (P+E). Left panel depicts number of infusions over 2hr as a function of dose of heroin (mg/kg/infusion). Right panel depicts AUC estimates as determined from the dose-response data. Vertical bars represent the SEM. Asterisks indicate significant differences between groups.