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

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.

Interactions Between Opioids and Dextroamphetamine on Locomotor Activity: Influence of an Opioid's Relative Efficacy at the Mu Receptor.

Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the behavioral effects of stimulants, whereas opioid receptor antagonists generally attenuate the behavioral effects of stimulants; however, less is known regarding the interactions between stimulants and opioids possessing low to intermediate efficacy at the mu receptor. The purpose of this study was to examine the role of an opioid's relative efficacy at the mu receptor in altering the behavioral effects of dextro(d-)amphetamine. To this end, opioids possessing a range of relative efficacy at the mu receptor were examined alone and in combination with cumulative doses of d-amphetamine on a test of open-field, locomotor activity in male rats. Levorphanol, buprenorphine, butorphanol, nalbuphine, (-)-pentazocine, (-)-metazocine, (-)-cyclazocine, (-)-NANM, and nalorphine increased the locomotor effects of d-amphetamine in either an additive or greater-than-additive manner according to an effect-additive model. Only the selective, high-efficacy kappa agonist, spiradoline, and the non-selective opioid receptor antagonist, naloxone, failed to increase the effects of d-amphetamine under the conditions examined. These data indicate that opioids possessing a large range of relative efficacy at the mu receptor, including those possessing very low relative efficacy, significantly increase the locomotor effects of d-amphetamine.