Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress.

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.

Recent Opioid Use Impedes Range Adaptation in Reinforcement Learning in Human Addiction.

BACKGROUND: Drugs like opioids are potent reinforcers thought to co-opt value-based decisions by overshadowing other rewarding outcomes, but how this happens at a neurocomputational level remains elusive. Range adaptation is a canonical process of fine-tuning representations of value based on reward context. Here, we tested whether recent opioid exposure impacts range adaptation in opioid use disorder, potentially explaining why shifting decision making away from drug taking during this vulnerable period is so difficult. METHODS: Participants who had recently (<90 days) used opioids (n = 34) or who had abstained from opioid use for ≥ 90 days (n = 20) and comparison control participants (n = 44) completed a reinforcement learning task designed to induce robust contextual modulation of value. Two models were used to assess the latent process that participants engaged while making their decisions: 1) a Range model that dynamically tracks context and 2) a standard Absolute model that assumes stationary, objective encoding of value. RESULTS: Control participants and ≥90-days-abstinent participants with opioid use disorder exhibited choice patterns consistent with range-adapted valuation. In contrast, participants with recent opioid use were more prone to learn and encode value on an absolute scale. Computational modeling confirmed the behavior of most control participants and ≥90-days-abstinent participants with opioid use disorder (75%), but a minority in the recent use group (38%), was better fit by the Range model than the Absolute model. Furthermore, the degree to which participants relied on range adaptation correlated with duration of continuous abstinence and subjective craving/withdrawal. CONCLUSIONS: Reduced context adaptation to available rewards could explain difficulty deciding about smaller (typically nondrug) rewards in the aftermath of drug exposure.

Trichostatin A, a histone deacetylase inhibitor, alleviates the emotional abnormality induced by maladaptation to stress in mice.

Recent reports have implied that aberrant biochemical processes in the brain are frequently accompanied by subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. The aim of the present study was to examine the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. We applied dosing schedules. In one schedule, from the 3rd day of stress exposure, mice were treated with TSA (1650 µM/4 µL, i.c.v.) immediately after the daily exposure to restraint stress. In the other schedule, from the 1st day of stress exposure, mice were treated with TSA 2 h before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using the hole-board test. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. On the other hand, no such stress adaptation was observed under chronic treatment with TSA immediately after daily stress exposure. A biochemical study showed that tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-HT) synthesis, was increased in midbrain containing raphe nuclei obtained from stress-adapted mice that were chronically treated with TSA 2 h before daily stress exposure. These findings suggest that an HDAC inhibitor may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress.

Tamsulosin facilitates depressive-like behaviors in mice: Involvement of endogenous glucocorticoids.

The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α1-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α1-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.

Putting things in context: Longitudinal relations between drinking contexts, drinking motives, and negative alcohol consequences.

Recent studies suggest that solitary (but not social) drinking may confer risk for negative alcohol consequences via beliefs about alcohol's ability to reduce tension, and explicit motivations to drink to cope with negative mood states. However, because prior studies are largely cross-sectional, it is unclear if tension reduction expectancies and drinking to cope are antecedents or consequences of solitary drinking. The current study aimed to address this gap in the literature using prospective data (3 waves across 12 months) from a sample of moderate to heavy drinking young adults. Data were drawn from a larger investigation of contextual influences on subjective alcohol response. Participants (N = 448) reported on alcohol use in multiple drinking contexts and tension reduction expectancies at baseline (T1), drinking motives at a 6-month follow-up (T2), and past-month negative alcohol consequences at a 12-month follow-up (T3). We examined potential indirect effects of drinking contexts on negative consequences operating through alcohol expectancies and drinking motives. Solitary drinking was indirectly associated with later negative consequences through stronger coping motives, although tension reduction expectancies did not serve as a significant mediator. Social drinking was not directly or indirectly related to later alcohol consequences. Results suggest that solitary drinking contexts confer risk for negative consequences through coping motives, and that these effects are invariant across sex, race, and ethnicity. These findings have important clinical implications as they suggest that targeting solitary drinkers for skills-based coping interventions may reduce risk for a developmental trajectory toward negative alcohol consequences. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Oxytocin-induced facilitation of learning in a probabilistic task is associated with reduced feedback- and error-related negativity potentials.

BACKGROUND: Feedback evaluation of actions and error response detection are critical for optimizing behavioral adaptation. Oxytocin can facilitate learning following social feedback but whether its effects vary as a function of feedback valence remains unclear. AIMS: The present study aimed to investigate whether oxytocin would influence responses to positive and negative feedback differentially or equivalently. METHODS: The present study employed a randomized, double-blind, placebo controlled within-subject design to investigate whether intranasal oxytocin (24 IU) influenced behavioral and evoked electrophysiological potential responses to positive or negative feedback in a probabilistic learning task. RESULTS: Results showed that oxytocin facilitated learning and this effect was maintained in the absence of feedback. Using novel stimulus pairings, we found that oxytocin abolished bias towards learning more from negative feedback under placebo by increasing accuracy for positively reinforced stimuli. Oxytocin also decreased the feedback-related negativity difference (negative minus positive feedback) during learning, further suggesting that it rendered the evaluation of positive and negative feedback more equivalent. Additionally, post-learning oxytocin attenuated error-related negativity amplitudes but increased the late error positivity, suggesting that it may lower conflict detection between actual errors and expected correct responses at an early stage of processing but at a later stage increase error awareness and motivation for avoiding them. CONCLUSIONS: Oxytocin facilitates learning and subsequent performance by rendering the impact of positive relative to negative feedback more equivalent and also by reducing conflict detection and increasing error awareness, which may be beneficial for behavioral adaption.

Parental Psychosocial Factors Moderate Opioid Administration Following Children's Surgery.

BACKGROUND: This investigation aimed to examine the impact of parental psychosocial variables on the administration of opioids to young children experiencing postoperative pain. METHODS: Participants in this longitudinal analysis were children ages 2-12 undergoing tonsillectomy with or without adenoidectomy and their parents. Parents completed validated instruments assessing trait anxiety, perceived stress, and coping style before surgery, and children and parents completed instruments assessing pain and administration of opioids and acetaminophen on days 1, 2, 3, and 7 at home after surgery. The structure of the data was such that parents and children completed multiple data assessments making the data multilevel (ie, days of data within dyads). To address this issue of data structure, multilevel modeling was used to analyze the dataset. RESULTS: Participants included 173 parent-child dyads (mean child age = 5.99 ± 2.51) recruited between 2012 and 2017. We found that parent-related psychosocial variables, such as trait anxiety, stress, and coping style, moderated the relationship between the child's pain and postoperative medication administration. Specifically, when predicting hydrocodone, the interactions between anxiety and pain and stress and pain were significant; when child pain was high, high-anxiety and high-stressed parents gave their children 19% and 12% more hydrocodone, respectively, compared to low-anxiety and low-stressed parents. When predicting acetaminophen, the interactions between anxiety and pain, a blunting coping style and pain, and a monitoring coping style and pain were significant. CONCLUSIONS: These results suggest the need to identify parents who experience high levels of perceived stress and trait anxiety and use appropriate interventions to manage stress and anxiety. This may ensure children receive optimal amounts of pain medication following surgery.

Differential effects of ethanol on behavior and GABAA receptor expression in adult zebrafish (Danio rerio) with alternative stress coping styles.

Variation in stress responses between individuals are linked to factors ranging from stress coping styles to sensitivity of neurotransmitter systems. Many anxiolytic compounds (e.g. ethanol) can increase stressor engagement through modulation of neurotransmitter systems and are used to investigate stress response mechanisms. There are two alternative suites of correlated behavioral and physiological responses to stressors (stress coping styles) that differ in exploration tendencies: proactive and reactive stress coping styles. By chronically treating individuals differing in stress coping style with ethanol, a GABA-acting drug, we assessed the role of the GABAergic system on the behavioral stress response. Specifically, we investigated resulting changes in stress-related behavior (i.e. exploratory behavior) and whole-brain GABAA receptor subunits (gabra1, gabra2, gabrd, & gabrg2) in response to a novelty stressor. We found that ethanol-treated proactive individuals showed lower stress-related behaviors than their reactive counterparts. Proactive individuals showed significantly higher expression of gabra1, gabra2, and gabrg2 compared to reactive individuals and ethanol treatment resulted in upregulation of gabra1 and gabrg2 in both stress coping styles. These results suggest that impacts of ethanol on stress-related behaviors vary by stress coping style and that expression of select GABAA receptor subunits may be one of the underlying mechanisms.

A Critical Review to Identify the Domains Used to Measure the Effect and Outcome of Adaptogenic Herbal Medicines.

Background: Phytoadaptogens are considered to be herbal medicines with a multi-target effect that strengthen organ systems compromised by stress. Although animal and laboratory studies have identified numerous molecular targets associated with adaptogenic activity, the non-specific characteristic of these herbal medicines has meant there is no known methods to accurately determine efficacy of adaptogens in humans. This critical review of the evidence aims to identify domains which have been used to measure the effect of adaptogens in humans, in order to create pathways for translating laboratory, animal, and clinical studies on adaptogens into practical applications in the future. Methods: EMBASE, AMED, PubMed, Cochrane Library, and WHO ICTRP databases were searched for randomized trials which examined known physiological actions of adaptogens. Results: Twenty-four studies were identified and critically appraised using the Jadad scale. The findings identified three broad categories of outcome measures, including cognitive, mood and biological measures. Conclusions: There was a great heterogeneity in data making it difficult to draw conclusions as to the most effective measurement tools to capture the holistic activity in humans. Cognitive measures hold promise as a reliable measurement tool when used in conjunction with other relevant tools. Further investigation is necessary to determine the most appropriate and diverse tools to measure the complex multi-target action of adaptogens.

The use of ketamine to cope with depression and post-traumatic stress disorder: A qualitative analysis of the discourses posted on a popular online forum.

Background: Because of the shortcomings of traditional pharmacotherapy for major depressive disorder and post-traumatic stress disorder (PTSD), there has been growing interest in the rapid mood-enhancing effect of ketamine. Objectives: To analyze what has been posted about ketamine use for dealing with self-reported depression and/or PTSD on one of the biggest international message boards on the internet. Methods: Qualitative study with online observation of threaded discussions on Bluelight. In-depth online searches were conducted in 2018. Twenty-nine threads, with a total of 708 units of analysis, were selected and subjected to content analysis, where, via a coding process, the units of analysis were organized into nodes. Results: Despite having several negative effects (e.g. dizziness, nausea and inability to talk), the examined discourses suggested that the use of ketamine to elevate mood was both efficient and worthwhile. Intranasal use was the most common route of administration mentioned. We traced how the mood enhancement caused by ketamine is perceived: the loss of pleasure disappears, as well as the depressed mood; the markedly diminished interest in activities vanishes and motivation comes back. From all the posts analyzed, only two reported negative outcomes (i.e. no mood-enhancing effect). The most mentioned adverse event was damage to the urinary bladder and the kidneys in cases of misuse. Conclusion: Although online research of user-generated content has its limitations in terms of reliability and validity, the present study adds relevant information on the use of ketamine for managing depression and PTSD, whether this use is done legally or not.

Perinatal fluoxetine exposure disrupts the circadian response to a phase-shifting challenge in female rats.

RATIONALE: Selective serotonin reuptake inhibitor (SSRI) antidepressants are increasingly prescribed during pregnancy. Changes in serotonergic signaling during human fetal development have been associated with changes in brain development and with changes in affective behavior in adulthood. The suprachiasmatic nucleus (SCN) is known to be modulated by serotonin and it is therefore assumed that SSRIs may affect circadian rhythms. However, effects of perinatal SSRI treatment on circadian system functioning in the offspring are largely unknown. OBJECTIVE: Our aim was to investigate the effects of perinatal exposure to the SSRI fluoxetine (FLX) on circadian behavior, affective behavior, and 5-HT1A receptor sensitivity in female rats. In addition, we studied the expression of clock genes and the 5-HT1A receptor in the SCN, as they are potentially involved in underlying mechanisms contributing to changes in circadian rhythms. RESULTS: Perinatal FLX exposure shortened the free-running tau in response to the 5-HT1A/7 agonist 8-OH-DPAT. However, FLX exposure did not alter anxiety, stress coping, and 5-HT1A receptor sensitivity. No differences were found in 5-HT1A receptor and clock genes Per1, Per2, Cry1, and Cry2 SCN gene expression. CONCLUSIONS: Perinatal FLX exposure altered the response to a phase-shifting challenge in female rats, whether this may pose health risks remains to be investigated.

Effects of Hemp Extract on Markers of Wellness, Stress Resilience, Recovery and Clinical Biomarkers of Safety in Overweight, But Otherwise Healthy Subjects.

We determined the effects of a commercially available, GRAS (Generally Recognized As Safe) by independent conclusion, CBD-containing hemp oil extract on stress resilience, perceived recovery, mood, affect, body composition, and clinical safety markers in healthy human subjects.Methods: Using a randomized, placebo-controlled, double-blind design, 65 overweight, but otherwise healthy men and women (35.2 ± 11.4 years, 28.5 ± 3.3 kg/m2) ingested either Hemp Oil Extract [Hemp, 60 mg/d PlusCBDTM Extra Strength Hemp Extract Oil (15 mg hemp-derived CBD)] or a placebo (PLA) every day for six weeks while continuing to follow their normal diet and physical activity patterns. Outcome variables included changes in stress resilience, a 14-item panel of various psychometric parameters, heart-rate variability, plasma chromogranin A, body composition, and general markers of health. Data were analyzed using mixed factorial ANOVA, t-tests with 95% confidence intervals, and effect sizes (ES).Results: HDL cholesterol significantly improved in the Hemp group (p = 0.004; ES = 0.75). No other statistically significant group x time interaction effects were observed. Statistical tendencies for between-group differences were found for 'I Get Pleasure From Life' (p = 0.06, ES = 0.48) and 'Ability to Cope with Stress' (p = 0.07, ES = 0.46). Sleep quality (Hemp, p = 0.005, ES = 0.54) and sleep quantity (Hemp, p = 0.01, ES = 0.58) exhibited significant within-group changes. All values for hepato-renal function, cardiovascular health, fasting blood lipids, and whole blood cell counts remained within normal clinical limits with no between-group differences over time being identified.Conclusions: Hemp supplementation improved HDL cholesterol, tended to support psychometric measures of perceived sleep, stress response, and perceived life pleasure and was well tolerated with no clinically relevant safety concerns. Registered at clinicaltrials.gov: NCT04294706.

Ecological momentary assessment of temptations and lapses in non-daily smokers.

RATIONALE: Little is known about relapse among non-daily, intermittent smokers (ITS), who have difficulty quitting, despite a lack of dependence. OBJECTIVES: To analyze situations associated with temptations to smoke and smoking lapses among ITS trying to maintain abstinence. METHODS: Participants were 130 initially abstinent ITS in the placebo arm of a smoking cessation study. EMA data captured participants' situations and states in temptations (n = 976), including those that eventuated in lapses (n = 147), for up to 6 weeks. Randomly timed assessments assessed background states (n = 11,446). Participants also reported coping performed to prevent lapses. Multilevel analyses compared temptations to background situations, and lapse episodes to resolved temptations. RESULTS: Temptations were marked by exposure to smoking cues, including others smoking, lax smoking restrictions, and alcohol consumption, as well as more negative affect. Lapses did not differ from resolved temptations in craving intensity, but were more often associated with smoking cues and availability of cigarettes, alcohol consumption, and worse affect, and were more often attributed to good moods. Both behavioral and cognitive coping responses were associated with avoiding lapsing, but behavioral coping had much larger effects. The effects of affective distress on lapse risk were mediated by its effects on coping. CONCLUSIONS: Smoking cues play a major role in ITS' temptations and lapses, perhaps indicating a degree of behavioral dependence. Affective distress also played a role in ITS lapses, undermining the idea that the affective distress seen in daily smokers' lapses is due to nicotine withdrawal. The data reinforce the important role of coping in preventing lapses.

Patterns of Alcohol Consumption and Drinking Motives Among Korean Medical Students.

BACKGROUND Physicians who have healthy lifestyles can provide quality healthcare to their patients and keep themselves healthy. There is little data on the prevalence of drinking behaviors and problems among East Asian medical students. Here, we explored alcohol use and drinking motives among medical students in Korea. MATERIAL AND METHODS A questionnaire-based, multicenter, cross-sectional study was carried out in 323 students from 5 medical colleges in Korea between July and October 2016. We used the Korean version of the Alcohol Use Disorders Identification Test (AUDIT) and an anonymous, self-administered questionnaire that included demographic characteristics, smoking status, consumption of alcohol, and drinking motives. RESULTS The mean AUDIT score was 9.8±7.5 for males and 6.3±5.4 for females. Heavy drinking (75.9%) and binge drinking (56.0%) were very high among Korean medical students. Female medical students drank as much as male students, and much more than other women. The probability that a student would be a binge drinker was 2.72 times higher for a smoker than a non-smoker. The scores for drinking frequency, alcohol intake at one time, heavy drinking, binge drinking, and alcohol dependence symptoms were highest in the group who had "enhancement drinking motives". CONCLUSIONS Heavy drinking and binge drinking are common among both male and female medical students in Korea and this behavior is associated with smoking and enhancement drinking motives. Medical schools should consider implementing effective interventions to prevent and reduce problem drinking among medical students.

The role of affect, emotion management, and attentional bias in young adult drinking: An experience sampling study.

RATIONALE: Coping with negative affect is central to several prominent etiological models of alcohol use. These models posit that alcohol use becomes negatively reinforced due to its ability to alleviate negative affect. However, there have been mixed findings when testing this association at the event-level. OBJECTIVES: The current experience sampling study sought to clarify this by testing if (1) within-person changes in the perceived difficulty of managing emotional distress is a significant predictor of alcohol consumption, over and above levels negative and positive affect and (2) whether acute changes in affective experiences give rise to increased attentional bias toward alcohol-related cues in the environment and if attentional bias mediates the association between difficulty managing emotions and alcohol consumption. Participants were 92 college students aged 18-25, who drink alcohol at least moderately. METHODS: Participants completed 28 days of experiencing sampling measures on their mood, difficulty managing emotions, alcohol-related attentional biases, and drinking. RESULTS: Findings showed that neither negative affect nor difficult managing emotions had significant effects on alcohol use. However, positive affect exhibited the expected associations with both attentional biases and drinking. State positive affect predicted acute increases in attentional biases and drinking, whereas trait positive affect was inversely associated with trait attentional biases and alcohol use. Alcohol-related attentional biases exhibited significant within-person variance; however, its relationship with drinking was only significant when the constructs were assessed concurrently at night and did not mediate the relationship between affect and alcohol use. CONCLUSIONS: Results highlight the importance of positive affect in this population.

Mediators of youth anxiety outcomes 3 to 12 years after treatment.

OBJECTIVE: Test changes in perceived coping efficacy, negative self-statements, and interpretive biases to threat during treatment as potential mediators of the relationship between randomly assigned treatment conditions and long-term anxiety follow-ups. Age at randomization was also tested as a moderator of mediational relationships. METHOD: Participants included 319 youth (ages 7-17) from the Child/Adolescent Multimodal Study (CAMS) who participated in a naturalistic follow-up beginning an average of 6.5 years after the end of the CAMS intervention. The intervention conditions included cognitive behavioral therapy (CBT; Coping Cat), pharmacotherapy (sertraline), combined CBT and sertraline, and pill placebo. Putative mediators were measured four times during the intervention phase. Follow-up consisted of four annual assessments of current anxiety. RESULTS: Reductions on a measure of interpretive bias to threat over the course of the combined condition intervention, as compared to the placebo condition, mediated anxiety outcomes at the first follow-up visit. This mediated effect was not significant for the CBT-only or sertraline-only conditions when compared to the placebo condition. No other significant mediated effects were found for putative mediators. Age did not significantly moderate any mediated effects. CONCLUSION: Changes in youth-reported interpretive biases to threat over the course of combined youth anxiety interventions, as compared to a placebo intervention, may be associated with lower anxiety an average of 6.5 years following treatment.

Alcohol exposure in utero disrupts cortico-striatal coordination required for behavioral flexibility.

Deficits in behavioral flexibility are a hallmark of multiple psychiatric, neurological, and substance use disorders. These deficits are often marked by decreased function of the prefrontal cortex (PFC); however, the genesis of such executive deficits remains understudied. Here we report how the most preventable cause of developmental disability, in utero exposure to alcohol, alters cortico-striatal circuit activity leading to impairments in behavioral flexibility in adulthood. We utilized a translational touch-screen task coupled with in vivo electrophysiology in adult mice to examine single unit and coordinated activity of the lateral orbital frontal cortex (OFC) and dorsolateral striatum (DS) during flexible behavior. Prenatal alcohol exposure (PAE) decreased OFC, and increased DS, single unit activity during reversal learning and altered the number of choice responsive neurons in both regions. PAE also decreased coordinated activity within the OFC and DS as measured by oscillatory field activity and altered spike-field coupling. Furthermore, PAE led to sustained connectivity between regions past what was seen in control animals. These findings suggest that PAE causes altered coordination within and between the OFC and DS, promoting maladaptive perseveration. Our model suggests that in optimally functioning mice OFC disengages the DS and updates the newly changed reward contingency, whereas in PAE animals, aberrant and persistent OFC to DS signaling drives behavioral inflexibility during early reversal sessions. Together, these findings demonstrate how developmental exposure alters circuit-level activity leading to behavioral deficits and suggest a critical role for coordination of neural timing during behaviors requiring executive function.

Hormonal contraceptive use predicts decreased perseverance and therefore performance on some simple and challenging cognitive tasks.

A growing body of research suggests that hormonal contraceptive (HC) use may be associated with lower self-control, as well as structural and functional differences in women's brains that could contribute to differences in perseverance on tasks requiring cognitive control. Here, we sought to extend this research by examining the relationship between HC use and college-aged women's perseverance (i.e., time spent) and performance on tasks requiring cognitive control. Across two studies, we find that, compared to naturally-cycling women, women using HCs display less perseverance on both simple (i.e., a spot-the-difference game) and challenging (i.e., Graduate Record Examination quantitative problems) tasks. Moreover, these differences in perseverance were found to predict performance decrements across tasks, with women taking HCs performing worse because they spent less time on the tasks. By demonstrating how HC use may influence perseverance and thereby performance, these results contribute to a growing body of research examining the unintended implications of HC use on cognition, learning, and memory.

Greater delay discounting and cannabis coping motives are associated with more frequent cannabis use in a large sample of adult cannabis users.

BACKGROUND: Self-regulation deficits expressed through a decreased ability to value future rewards (delay discounting (DD)) and impaired emotion regulation (negative urgency (NU), cannabis coping motives (CCM), and anxiety sensitivity (AS)) relate to more frequent or problematic cannabis use. However, there is a need to better understand how self-regulation and emotion regulation constructs reflect competition between deliberative and reactive systems that drive individual differences in cannabis use patterns. Further, few studies assess frequency of cannabis use within and across days of use, which may obscure differentiation of individual differences. METHODS: In a large national sample of 2545 cannabis users, Latent Class Analysis was used to derive participant sub-classes based on two frequency indices, self-reported cannabis use days and times cannabis was used per day. Three classes emerged: Low (1-9 days/month, 1 time/day; 23 %), moderate (10-29 days/month, 2-3 times/day; 41 %), and high (30 days/month, ≥4 times/day; 36 %). Relationships among frequency classes and emotional regulation and impulsivity were assessed with a multinomial logistic regression. RESULTS: Higher frequency use was associated with greater DD (χ2 = 6.0, p = .05), greater CCM (χ2 = 73.3, p < .001), and lower cognitive AS (χ2 = 12.1, p = .002), when controlling for demographics, tobacco use, and number of cannabis administration methods. Frequency class and NU were not significantly associated. CONCLUSIONS: Identifying meaningful patterns of cannabis use may improve our understanding of individual differences that increase risk of frequent or problematic cannabis use. Excessive delay discounting and using cannabis to cope with negative affect may be relevant targets for treatments designed to reduce cannabis use.

Lasting Impact of Chronic Adolescent Stress and Glucocorticoid Receptor Selective Modulation in Male and Female Rats.

Adolescent animals are vulnerable to the effects of stress on brain development. We hypothesized that long-term effects of adolescent chronic stress are mediated by glucocorticoid receptor (GR) signaling. We used a specific GR modulator (CORT108297) to pharmacologically disrupt GR signaling in adolescent rats during exposure to chronic variable stress (CVS). Male and female rats received 30 mg/kg of drug during a 2-week CVS protocol starting at PND46. Emotional reactivity (open field) and coping behaviors (forced swim test (FST)) were then tested in adulthood, 5 weeks after the end of the CVS protocol. Blood samples were collected two days before FST and serial samples after the onset of the swim test to determine baseline and stress response levels of HPA hormones respectively. Our results support differential behavioral, physiological and stress circuit reactivity to adolescent chronic stress exposure in males and females, with variable involvement of GR signaling. In response to adolescent stress, males had heightened reactivity to novelty and exhibited marked reduction in neuronal excitation following swim stress in adulthood, whereas females developed a passive coping strategy in the FST and enhanced HPA axis stress reactivity. Only the latter effect was attenuated by treatment with the GR modulator C108297. In summary, our data suggest that adolescent stress differentially affects emotional behavior and circuit development in males and females, and that GR manipulation during stress can reverse at least some of these effects.