Shame and Emotion Dysregulation as Pathways to Posttraumatic Stress Symptoms Among Women With a History of Interpersonal Trauma.

Women who have survived interpersonal trauma are at elevated risk of developing posttraumatic stress disorder (PTSD), and potentially modifiable factors that may be targeted in treatment warrant further investigation. This study examined a pathway from interpersonal trauma to PTSD symptoms via emotion dysregulation and shame in a large non-clinical sample of women. The sample comprised 380 women, aged 18 to 59 years (M = 31.70, standard deviation = 10.06), all of whom had a history of interpersonal trauma. Participants completed the Experience of Shame Scale, the Difficulties in Emotion Regulation Scale-Short Form, and the Life Events Checklist for DSM-5. A serial and parallel process model with interpersonal trauma as a predictor of PTSD symptoms, emotional dysregulation and facets of shame as intermediary variables, was analyzed using Statistical Package for Social Sciences Statistics PROCESS Model 81with bias-corrected bootstrap tests of indirect effects. Non-interpersonal trauma was included as a covariate. Interpersonal trauma, emotion dysregulation, and characterological and bodily shame were significantly and directly associated with PTSD symptoms, together explaining 59% of the variation in PTSD symptoms. While emotion dysregulation was associated with behavioral shame, interpersonal trauma was not associated with behavioral shame, nor was behavioral shame associated with PTSD symptoms. Tests of indirect effects supported a pathway from interpersonal trauma to PTSD symptoms via emotion dysregulation and characterological and bodily shame. These findings suggest interventions that are particularly effective at reducing emotion dysregulation and characterological and bodily shame, such as compassion and acceptance-based approaches, may complement evidence-based PTSD interventions when working with women who have survived interpersonal trauma.

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.

Demand and cross-price elasticity of cocaine and social contact in a free-operant procedure of nonexclusive choice.

Research examining the social determinants of addiction has advanced significantly with the recent development of preclinical models of drug use and the social environment. These models reveal that drug use and social contact compete with one another for behavioral expression in discrete-trial choice procedures using concurrent schedules of reinforcement. The purpose of this study was to determine how concurrent access to cocaine and a social partner influences the demand for each alternative under free-operant conditions in which responding maintained by each reinforcer is independent and nonexclusive of the other. To this end, male rats were trained under a free-operant, concurrent schedule of reinforcement in which responding maintained by cocaine and access to a social partner operated independently of one another. Measures of economic demand (e.g., intensity, Omax, cross-price elasticity) were determined by manipulating the response requirement (i.e., fixed ratio value) across sessions. Tests were conducted in which the social partner was either treated or not treated with cocaine to determine whether the intoxication state of the partner influenced demand. The principal findings of this study are (1) demand for a cocaine-treated partner is greater than demand for a cocaine-free partner, (2) demand for cocaine is greater in the presence of a cocaine-treated partner than a cocaine-free partner, and (3) concurrent access to cocaine decreases demand for social contact. Notably, measures of cross-price elasticity indicated that social contact is a robust economic substitute for cocaine.

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.

The effects of artificially induced proestrus on heroin intake: A critical role for estradiol.

Heroin intake decreases markedly during proestrus in normally cycling female rats; however, it is not known whether estradiol, progesterone, or both hormones are responsible for these decreases in heroin intake. The purpose of the present study was to examine the roles of estradiol and progesterone in heroin intake by artificially inducing a proestrus state in ovariectomized rats. To this end, ovariectomized female rats were implanted with intravenous catheters and trained to self-administer heroin (0.0075 mg/kg/infusion) on a fixed ratio (FR1) schedule of reinforcement. After 1 week of training, rats were tested at weekly intervals with estradiol (0.005 mg, sc) or vehicle 22 hr before a test session and progesterone (0.125 mg, sc) or vehicle 0.5 hr before a test session to artificially mimic the naturally occurring hormone concentrations characteristic of late proestrus. Administration of estradiol 22 hr prior to testing and progesterone 0.5 hr prior to testing significantly reduced heroin intake relative to the previous training day and vehicle control. It is interesting that this same effect was observed when only estradiol, but not progesterone, was administered. These data suggest that estradiol but not progesterone is responsible for the proestrus-induced decreases in heroin intake previously reported in normally cycling female rats. These findings differ from those reported previously with stimulants and suggest that estrogen-based pharmacotherapies may be of value to women with opioid use disorder. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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.

Social Contact Reinforces Cocaine Self-Administration in Young Adult Male Rats: The Role of Social Reinforcement in Vulnerability to Drug Use.

Drug-using peers are recognized as a leading factor influencing drug use among adolescents and young adults. One mechanism by which peers influence drug use is by providing social reinforcement for using drugs. Social reinforcement may be provided in multiple ways, including by making social contact contingent on drug use (i.e., an individual must use drugs to gain/maintain access to a peer). The purpose of this study was to develop a preclinical model in which intravenous cocaine self-administration was positively reinforced by access to a social partner. Young adult male rats were trained to self-administer cocaine in operant conditioning chambers with a guillotine door that could be opened to an adjacent compartment housing either a social partner or a non-social stimulus. Once cocaine self-administration was established, the guillotine door was activated, and cocaine intake was reinforced by brief access to either a social (age- and sex-matched peer) or non-social (black-and-white athletic sock) stimulus. Contingent access to a social partner rapidly increased cocaine self-administration. Total cocaine intake was 2- to 3-fold greater in rats assigned to the social versus non-social condition across a 100-fold dose range. Cocaine intake rapidly increased when rats in the original non-social group were later provided with social partners, whereas cocaine intake resisted change and remained elevated when rats in the original social group had their partners removed. These data indicate that contingent access to a social partner increases drug intake and suggest that social reinforcement may represent a vulnerability factor that is particularly resistant to psychosocial interventions.

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.

The Effects of Drugs on Behavior Maintained by Social Contact: Role of Monoamines in Social Reinforcement.

Drug use is highly concordant among members of adolescent and young adult peer groups. One potential explanation for this observation is that drugs may increase the reinforcing effects of social contact, leading to greater motivation to establish and maintain contact with other members of the peer group. Several classes of drugs, particularly drugs that increase synaptic dopamine, increase the reinforcing effects of contextual stimuli, but the extent to which these drugs enhance the reinforcing effects of social contact is not known. The purpose of this study was to determine the extent to which drugs that increase synaptic dopamine, norepinephrine, and serotonin enhance the positive reinforcing effects of social contact. To this end, male and female Long-Evans rats were pretreated with acute doses of the selective dopamine reuptake inhibitor, WIN-35,428, the selective norepinephrine reuptake inhibitor, atomoxetine, the selective serotonin reuptake inhibitor, fluoxetine, the non-selective monoamine reuptake inhibitor, cocaine, and the non-selective monoamine releasers d-amphetamine and (±)-MDMA. Ten minutes later, the positive reinforcing effects of 30-s access to a same-sex social partner was examined on a progressive ratio schedule of reinforcement. To determine whether the reinforcement-altering effects of these drugs were specific to the social stimulus, the reinforcing effects of a non-social stimulus (30-s access to an athletic sock of similar size and coloring as another rat) was determined in control subjects. WIN-35,428, d-amphetamine, and cocaine, but not atomoxetine, fluoxetine, or MDMA, dose-dependently increased breakpoints maintained by a social partner under conditions in which responding maintained by a non-social stimulus was not affected. These data indicate that increases in extracellular dopamine, but not extracellular norepinephrine or serotonin, increases the positive reinforcing effects of social contact in both male and female rats. These data also provide support for the hypothesis that some drugs with high abuse liability increase the motivation to establish and maintain contact with social peers.

Adolescent exposure to fluoxetine impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats.

The effects of chronic adolescent fluoxetine (FLX, Prozac®) exposure on adult cognition are largely unknown. We used a serial multiple choice (SMC) task to characterize the effects of adolescent FLX exposure on rat serial pattern learning in adulthood. Male rats were exposed to either 1.0, 2.0, or 4.0 mg/kg/day FLX for five consecutive days each week for five weeks during adolescence, followed by a 35-day drug-free period. As adults, the rats were trained in a task that required them to learn a highly structured sequential pattern of responses in an octagonal chamber for water reinforcement. In a transfer phase, the terminal element of the pattern was replaced by a violation element that was inconsistent with previously learned pattern structure. Results indicated that adolescent FLX exposure caused differential learning deficits for different types of elements in the serial pattern. Adolescent exposure to 1.0 or 4.0 mg/kg/day FLX, but not 2.0 mg/kg/day FLX, impaired chunk-boundary element learning, which is known to be mediated by stimulus-response (S-R) learning. All three doses of FLX impaired violation element learning, which is known to be mediated by multiple-cue learning. FLX did not impair within-chunk element learning, which is known to be mediated by rule-learning mechanisms. The results indicate that adolescent FLX exposure produced multiple cognitive impairments that were detectable in adulthood long after drug exposure ended.

Serial pattern retention in male and female rats.

Serial pattern learning is a model paradigm for studying parallel-processing in complex learning in rats. The current experiment extends the paradigm to the study of sequential memory by examining forgetting curves for the component element types that make up a serial pattern. Adult male and female rats were trained in a serial multiple choice (SMC) task in which rats learned a serial pattern of nose-poke responses in a circular array of 8 receptacles mounted on the walls of an octagonal operant chamber. The pattern was 123-234-345-456-567-678-781-818, where digits represent the clockwise positions of successive correct receptacles. Previous work has shown that chunk-boundary elements (the first element of each 3-element chunk), within-chunk elements (the second and third elements in all but the last chunk), and the violation element (the last element of the pattern) are learned via different cognitive mechanisms. After each rat was trained to an 85% correct performance criterion on the violation element, we then assessed serial pattern retention at 24-h, 2-week, and 4-week retention intervals. For chunk-boundary and within-chunk elements, forgetting was observed only at the 4-week retention interval. Sex differences were observed; females performed better than males on within-chunk elements at 24-h and 4-week retention intervals. For the violation element, significant forgetting was observed earlier at the 2-week retention interval as well as at the 4-week retention interval. Thus, pattern elements that were learned slower were forgotten faster. The experiment provides a proof of concept for evaluating forgetting curves separately for the multiple memory systems rats appear to employ concurrently in this paradigm, a method that may prove useful in characterizing the impact of relevant neurobiological manipulations on forgetting in multiple sequential memory systems.