The effects of gonadal hormones on heroin Self-Administration in male gonadectomized rats.

RATIONALE: Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. OBJECTIVES: The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. METHODS: Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75 mg, sc), estradiol (0.0005 or 0.005 mg, sc), progesterone, (0.0125 or 0.125 mg, sc), or their vehicles. After 14 days of chronic treatment, a dose-effect curve was determined for heroin (0.0003-0.03 mg/kg/infusion) over the course of one week. RESULTS: Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125 mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. CONCLUSIONS: These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder.

Sex differences in opioid receptor mediated effects: Role of androgens.

An abundance of data indicates there are sex differences in endogenous opioid peptides and opioid receptors, leading to functional differences in sensitivity to opioid receptor mediated behaviors between males and females. Many of these sex differences are mediated by the effects of gonadal hormones on the endogenous opioid system. Whereas much research has examined the role of ovarian hormones on opioid receptor mediated endpoints, comparatively less research has examined the role of androgens. This review describes what is currently known regarding the influence of androgens on opioid receptor mediated endpoints and how androgens may contribute to sex differences in these effects. The review also addresses the clinical implications of androgenic modulation of opioid receptor mediated behaviors and suggests future lines of research for preclinical and clinical investigators. We conclude that further investigation into androgenic modulation of opioid receptor mediated effects may lead to new options for addressing conditions such as chronic pain and substance use disorders.

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 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.

Does Red Cell Distribution Width Predict Outcome in Traumatic Brain Injury: Comparison to Corticosteroid Randomization After Significant Head Injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability. The role of red cell distribution width (RDW) as a prognostic biomarker for outcome in TBI patients is unknown. Based on the corticosteroid randomization after significant head injury (CRASH) trial database, a prognosis calculator (CRASH) has been developed for outcome prediction in TBI. The objectives of this study are to investigate the association between RDW on day 1 of TBI and outcome, and to compare outcome prediction from RDW to that from CRASH. METHODS: We performed a retrospective review of patients with TBI and a Glasgow coma scale (GCS) score of 14 or less. Day 1 RDW and CRASH data were extracted. CRASH was calculated for each patient. Outcome was defined as mortality at 14 days and GOS at 6 months, with poor outcome defined as GOS of 1 - 3. Patients were stratified according to RDW values into six groups, and according to CRASH values into six groups. RESULTS: A total of 416 patients with TBI were included, with 339 survivors (S) and 77 non-survivors (NS). Compared to survivors, non-survivors were of similar age in years (58 ± 23 vs. 58 ± 23, P = 1.0), had lower GCS scores (5 ± 3 vs. 12 ± 3, P = 0.0001), similar RDW (14.0 ± 1.2 vs. 13.9 ± 1.5, P = 0.6), and higher CRASH values (68 ± 26 vs. 24 ± 22, P = 0.0001). Estimating the receiver-operating characteristic (ROC) area under the curve (AUC) showed that CRASH was a significantly better predictor of mortality compared to RDW (AUC = 0.91 ± 0.01 for CRASH compared to 0.66 ± 0.03 for RDW; P < 0.0001). In addition, CRASH was a better predictor of neurologic outcome compared to RDW (AUC = 0.85 ± 0.02 for CRASH compared to 0.76 ± 0.03 for RDW; P = 0.005). CONCLUSIONS: CRASH calculator was a strong predictor of mortality in patients with TBI. RDW on day 1 did not differ between survivors and non-survivors, and was a poor predictor of mortality. Both RDW on day 1 and CRASH calculator are good predictors of 6-month outcome in TBI patients, although CRASH calculator remains a better predictor.