The effects of chronic estradiol treatment on opioid self-administration in intact female rats

Abstract

Heroin intake decreases significantly during proestrus in normally cycling female rats, and this effect is mediated by endogenous estradiol but not endogenous progesterone. The purpose of this study was to determine whether chronic administration of exogenous estradiol decreases intake of the semi-synthetic opioid, heroin, and the fully synthetic opioid, remifentanil, in intact female rats. Normally cycling female rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Rats were treated chronically with daily administration of either a low dose of estradiol (0.5 mcg, sc), a high dose of estradiol (5.0 mcg, sc), or vehicle (peanut oil, sc). After two weeks of heroin self-administration training, dose-effect curves were determined for both heroin and remifentanil. Chronic administration of estradiol non-significantly decreased heroin intake and significantly decreased remifentanil intake. Estradiol-induced decreases in remifentanil intake were dose-dependent, characterized by large effect sizes, and greatest in rats treated with the high dose of estradiol. These data indicate that chronic estradiol administration decreases opioid intake in intact female rats with medium to large effect sizes across opioids. These findings suggest that estrogen-based pharmacotherapies may represent a novel treatment approach for women with opioid use disorder.

Keywords: Estradiol; Estrogen; Estrous cycle; Opioid; Self-administration.

Figure 1.

Heroin intake during the last five days of training in female rats treated chronically with vehicle (n = 25), 0.5 mcg estradiol (n = 19), or 5.0 mcg estradiol (n = 25). Left panel depicts number of infusions over 2 hr as a function of training session prior to testing. Right panel depicts total number of infusions over the five sessions. Vertical bars represent the SEM.

Figure 2.

Heroin intake during testing in female rats treated chronically with vehicle (n = 25), 0.5 mcg estradiol (n = 19), or 5.0 mcg estradiol (n = 25). Left panel depicts number of infusions over 2 hr as a function of dose of heroin (mg/kg/infusion) or saline (SAL). Right panel depicts AUC estimates as determined from the dose-response data. Vertical bars represent the SEM.

Figure 3.

Remifentanil intake during testing in female rats treated chronically with vehicle (n = 24), 0.5 mcg estradiol (n = 19), or 5.0 mcg estradiol (n = 24). Left panel depicts number of infusions over 2 hr as a function of dose of remifentanil (mg/kg/infusion) or saline (SAL). Right panel depicts AUC estimates as determined from the dose-response data. Vertical bars represent the SEM. Asterisk indicates significant difference between groups.