Lack of evidence for positive reinforcing and prosocial effects of MDMA in pair-housed male and female rats.

3,4-Methylenedioxymethamphetamine (MDMA) is classified as an entactogen, producing feelings of emotional openness and relatedness. One unique feature of MDMA is that people tend to selectively take this drug in social and/or intimate situations. Although MDMA is recognized as having abuse liability, preclinical studies report that it has weak reinforcing effects in animals. The objective of this study was to characterize the positive reinforcing and prosocial effects of MDMA in a translational model of the social environment in which two rats have simultaneous and contingent access to MDMA in close physical proximity. To this end, MDMA self-administration was examined on both fixed and progressive ratio schedules of reinforcement in six groups of rats: (1) isolated males, (2) isolated females, (3) male-male dyads, (4) female-female dyads, (5) male-female dyads, and (6) female-male dyads. For pair-housed rats, data from both rats were analyzed. Next, social preferences were examined in a partner preference test. MDMA failed to produce positive reinforcing effects under all conditions examined. Across a 30-fold dose range (0.01-1.0 mg/kg/infusion), MDMA did not maintain higher responding than saline on both schedules of reinforcement and in all groups tested. In partner preference tests, a history of shared exposure to MDMA did not establish a social preference, and acute administration of MDMA failed to establish a preference for another MDMA-treated rat. These data suggest that social contact does not increase the positive reinforcing effects of MDMA in rats, and that neither contingent nor noncontingent MDMA administration establishes a social preference in rats.

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

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.

The effects of strain and estrous cycle on heroin- and sugar-maintained responding in female rats.

Heroin intake decreases during the proestrus phase of the estrous cycle in female, Long-Evans rats. The purpose of this study was to (1) determine if proestrus-associated decreases in heroin intake extend across rat strains and (2) determine if proestrus-associated decreases in responding extend to a nondrug reinforcer. Female rats were implanted with intravenous catheters and trained to self-administer heroin. Estrous cycle was tracked daily for the duration of the study. During testing, Lewis, Sprague Dawley, and Long-Evans rats self-administered low (0.0025 mg/kg) and high (0.0075 mg /kg) doses of heroin and then self-administered sugar on fixed ratio (FR1) schedules of reinforcement. Heroin intake decreased significantly during proestrus in all three rat strains under at least one dose condition; however, sugar intake did not decrease during proestrus in any strain. These data suggest that responding maintained by heroin, but not a nondrug reinforcer, significantly decreases during proestrus in female rats and that these effects are consistent across rat strain.

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.