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BACKGROUND: Previous studies have described blunted stress hormone responses after pharmacological activation of the hypothalamic-pituitary-adrenal (HPA) axis in sober alcoholics. The aim of the present study was to compare ACTH, cortisol, and prolactin responses to a psychological stressor in abstinent alcohol-dependent subjects matched to healthy control subjects. METHODS: Individuals who met DSM-IV diagnostic criteria for a history of alcohol dependence but not for other axis I disorders were included in the study (n = 18; mean duration of abstinence +/- SEM, 3.5 +/- 5.7 years). Social drinkers (n = 23) served as control subjects. The sober alcohol-dependent and control subjects were matched for demographic measures including levels of stress symptoms. All subjects underwent the Trier Social Stress Test (TSST), a laboratory-based psychological stressor. Prestress and poststress plasma ACTH, cortisol, and prolactin levels, as well as a self-report measure of anxiety (State-Trait Anxiety Inventory), were obtained. RESULTS: Nondepressed, abstinent alcoholics and control subjects did not differ with regard to age, racial composition, or baseline or poststress ratings of anxiety. Whereas ACTH and cortisol levels increased in response to the TSST, prolactin levels did not. Stress hormone response curves for the three hormones did not differ between the alcoholics and control subjects. CONCLUSIONS: When matched for levels of stress, a laboratory-based psychological stress test did not induce differential hormone response curves for abstinent alcoholics and control subjects. [ABSTRACT FROM AUTHOR]

Childhood and adolescent stress increase the risk of postpartum depression (PPD), often providing an increased probability of treatment refractoriness. Nevertheless, the mechanisms linking childhood/adolescent stress to PPD remain unclear. Our study investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and postpartum behaviors in mice and humans. Adolescent social isolation prolonged glucocorticoid elevation, leading to long-lasting postpartum behavioral changes in female mice. These changes were unresponsive to current PPD treatments but improved with post-delivery glucocorticoid receptor antagonist treatment. Childhood/adolescent stress significantly impacted HPA axis dysregulation and PPD in human females. Repurposing glucocorticoid receptor antagonists for some cases of treatment-resistant PPD may be considered., Competing Interests: Competing Interests Statement The authors declare no competing interests.

Background: Alcohol use disorder (AUD) affects 283 million people worldwide and its prevalence is increasing. Despite the role of the cerebellum in executive control and its sensitivity to alcohol, few studies have assessed its involvement in AUD-relevant functional networks. The goal of this study is to compare resting-state functional connectivity (FC) patterns in abstinent adults with a history of AUD and controls (CTL). We hypothesized that group differences in cerebro-cerebellar FC would be present, particularly within the frontoparietal/executive control network (FPN)., Methods: Twenty-eight participants completed a resting-state functional magnetic resonance imaging (rsfMRI) study. CTL participants had no history of AUD, comorbid psychological conditions, or recent heavy drinking and/or drug use. AUD participants had a history of AUD, with sobriety for at least 30 days prior to data collection. Multivariate pattern analysis, an agnostic, whole-brain approach, was used to identify regions with significant differences in FC between groups. Seed-based analyses were then conducted to determine the directionality and extent of these FC differences. Associations between FC strength and executive function were assessed using correlations with Wisconsin Card Sorting Test (WCST) performance., Results: There were significant group differences in FC in nodes of the FPN, ventral attention network, and default mode network. Post hoc analyses predominantly identified FC differences within the cerebro-cerebellar FPN, with AUD showing significantly less FC within the FPN. In AUD, FC strength between FPN clusters identified in the multivariate pattern analysis (MVPA) analysis (Left Crus II, Right Frontal Cortex) was positively associated with performance on the WCST., Conclusions: Our results show less engagement of the FPN in individuals with AUD than in CTL. FC strength within this network was positively associated with performance on the WCST. These findings suggest that long-term heavy drinking alters cerebro-cerebellar FC, particularly within networks that are involved in executive function., (© 2023 Research Society on Alcohol.)

Objective: To analyze associations between adiposity and the renin-angiotensin-aldosterone system (RAAS) in a large African American (AA) cohort., Methods: Cross-sectional associations of adiposity (body mass index [BMI], waist circumference [WC], waist:height ratio, waist:hip ratio, leptin, adiponectin, leptin:adiponectin ratio [LAR], subcutaneous [SAT] and visceral adipose tissue [VAT], and liver attenuation [LA]) with aldosterone, plasma renin activity (renin), and aldosterone:renin ratio (ARR) were assessed in the Jackson Heart Study using adjusted linear regression models., Results: A 1-SD higher BMI was associated with a 4.8 % higher aldosterone, 9.4 % higher renin, and 5.0 % lower ARR (all p < 0.05). Log-leptin had the largest magnitude of association with renin (30.2 % higher) and ARR (9.6 % lower), while the strongest association of aldosterone existed for log-LAR (15.3 % higher) (all 1-SD, p < 0.05). SAT was only associated with renin. VAT was associated with higher aldosterone, renin, and ARR. Liver fat was associated with aldosterone and renin, but not ARR. Associations of WC, BMI, and SAT with aldosterone were greater in men while the association with VAT was greater in women (p-interactions < 0.05)., Conclusion: Multiple measures of adiposity are associated with the RAAS in AAs. Further studies should examine the role of RAAS in obesity-driven cardiometabolic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Importance: A combination of diabetes, coronary heart disease (CHD), and stroke has multiplicative all-cause mortality risk compared with any individual morbidity in White populations, but there is a lack of studies in Black populations in the US., Objective: To examine the association of cardiometabolic multimorbidity (diabetes, stroke, and CHD) individually and collectively with all-cause and CHD mortality., Design, Setting, and Participants: This cohort study included Black adults in the Jackson Heart Study followed over a median of 15 years. Baseline examinations were performed between 2000 and 2004, with follow-up on all-cause and CHD mortality through May 31, 2018. Participants were categorized into mutually exclusive groups at baseline: (1) free of cardiometabolic morbidity, (2) diabetes, (3) CHD, (4) stroke, (5) diabetes and stroke, (6) CHD and stroke, (7) diabetes and CHD, and (8) diabetes, stroke, and CHD. Data were analyzed from 2019 to 2021., Exposure: Cardiometabolic disease alone or in combination., Main Outcomes and Measures: The main outcomes were all-cause mortality and CHD mortality. Cox models estimated hazard ratios (HRs) with 95% CIs adjusted for sociodemographic and cardiovascular risk factors., Results: Among 5064 participants (mean [SD] age, 55.4 [12.8] years; 3200 [63%] women) in the Jackson Heart Study, 897 (18%) had diabetes, 192 (4%) had CHD, and 104 (2%) had a history of stroke. Among participants with cardiometabolic morbidities, the crude all-cause mortality rates were lowest for diabetes alone (24.4 deaths per 1000 person-years) and highest for diabetes, CHD, and stroke combined (84.1 deaths per 1000 person-years). For people with only 1 cardiometabolic morbidity, risk for all-cause mortality was highest for people with stroke (HR, 1.74; 95% CI, 1.24-2.42), followed by CHD (HR, 1.59 (95% CI, 1.22-2.08) and diabetes (HR, 1.50; 95% CI, 1.22-1.85), compared with no cardiometabolic morbidities. There were also increased risks of mortality with combinations of diabetes and stroke (HR, 1.71; 95% CI, 1.09-2.68), CHD and stroke (HR, 2.23; 95% CI, 1.35-3.69), and diabetes and CHD (HR, 2.28; 95% CI, 1.65-3.15). The combination of diabetes, stroke, and CHD was associated with the highest all-cause mortality (HR, 3.68; 95% CI, 1.96-6.93). Findings were similar for CHD mortality, but with a larger magnitude of association (eg, diabetes, stroke, and CHD: HR, 13.52; 95% CI, 3.38-54.12)., Conclusions and Relevance: In this cohort study, an increasing number of cardiometabolic multimorbidities was associated with a multiplicative increase in risk of all-cause mortality among Black adults, with a greater magnitude of association for CHD mortality.

Context: Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to accelerated aging; however, while the link between chronic GC exposure and disease onset is well established, the underpinning mechanisms are not clear., Objective: We explored the potential nexus between GCs or stress exposure and telomere length., Methods: In addition to rats exposed to 3 weeks of chronic stress, an iatrogenic mouse model of Cushing syndrome (CS), and a mouse neuronal cell line, we studied 32 patients with CS and age-matched controls and another cohort of 75 healthy humans., Results: (1) Exposure to stress in rats was associated with a 54.5% (P = 0.036) reduction in telomere length in T cells. Genomic DNA (gDNA) extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P = 0.006). (2) Mice exposed to corticosterone had a 61.4% reduction in telomere length in blood gDNA (P = 5.75 × 10-5) and 58.8% reduction in telomere length in the dentate gyrus (P = 0.002). (3) We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P = 0.006). There was a 17.8% reduction in telomere length in cured CS patients, which was not different from that of healthy controls (P = 0.08). For both cured and active CS, telomere length correlated significantly with duration of hypercortisolism (R2 = 0.22, P = 0.007). (4) There was a 27.6% reduction in telomere length between low and high tertiles in bedtime cortisol levels of healthy participants (P = 0.019)., Conclusion: Our findings demonstrate that exposure to stress and/or GCs is associated with shortened telomeres, which may be partially reversible., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Allostatic load (AL) refers to the cumulative "wear and tear" on an organism throughout its lifetime. One of the primary contributing factors to AL is prolonged exposure to stress or its primary catabolic agent cortisol. Chronic exposure to stress or cortisol is associated with numerous diseases, including cardiovascular disease, metabolic disorders, and psychiatric disorders. Therefore, a molecular marker capable of integrating a past history of cortisol exposure would be of great utility for assessing disease risk. To this end, we recruited 87 healthy males and females of European ancestry between 18 and 60 years old, extracted genomic DNA and RNA from leukocytes, and implemented a gene-centric DNA enrichment method coupled with bisulfite sequencing and RNA-Seq of total RNA for the determination of genome-wide methylation and gene transcription, respectively. Sequencing data were analyzed against awakening and bedtime cortisol data to identify differentially methylated regions (DMRs) and CpGs (DMCs) and differentially expressed genes (DEGs). Six candidate DMCs ( p unadjusted < 0.005) and nine DEGs ( p unadjusted < 0.0005) were used to construct a prediction model that could capture past 30+ days of both bedtime and awakening cortisol levels. Utilizing a cross-validation approach, we obtained a regression coefficient of R 2 = 0.308 for predicting continuous awakening cortisol and an area under the curve (AUC) = 0.753 for dichotomous (high vs. low tertile) awakening cortisol, and R 2 = 0.224 and AUC = 0.723 for continuous and dichotomous bedtime cortisol levels, respectively. To our knowledge, the current study represents the first attempt to identify genome-wide predictors of cortisol exposure that utilizes both methylation and transcription targets. The utility of our approach needs to be replicated in an independent cohort of samples for which similar cortisol metrics are available.

Background: The renin-angiotensin-aldosterone system (RAAS) is an important driver of blood pressure (BP), but the association of the RAAS with ambulatory BP (ABP) and ABP monitoring phenotypes among African Americans has not been assessed., Methods: ABP and ABP monitoring phenotypes were assessed in 912 Jackson Heart Study participants with aldosterone and plasma renin activity (PRA). Multivariable linear and logistic regression analyses were used to analyze the association of aldosterone and PRA with clinic, awake, and asleep systolic BP and diastolic BP (DBP) and ABP monitoring phenotypes, adjusting for important confounders., Results: The mean age of participants was 59±11 years and 69% were female. In fully adjusted models, lower log-PRA was associated with higher clinic, awake, and asleep systolic BP and DBP (all P <0.05). A higher log-aldosterone was associated with higher clinic, awake, and asleep DBP (all P <0.05). A 1-unit higher log-PRA was associated with lower odds of daytime hypertension (odds ratio [OR] 0.59 [95% CI, 0.49-0.71]), nocturnal hypertension (OR, 0.68 [95% CI, 0.58-0.79]), daytime and nocturnal hypertension (OR, 0.59 [95% CI, 0.48-0.71]), sustained hypertension (OR, 0.52 [95% CI, 0.39-0.70]), and masked hypertension (OR 0.75 [95% CI, 0.62-0.90]). A 1-unit higher log-aldosterone was associated with higher odds of nocturnal hypertension (OR, 1.38 [95% CI, 1.05-1.81]). Neither PRA nor aldosterone was associated with percent dipping, nondipping BP pattern, or white-coat hypertension. Patterns for aldosterone:renin ratio were similar to patterns for PRA., Conclusions: Suppressed renin activity and higher aldosterone:renin ratios were associated with higher systolic BP and DBP in the office and during the awake and asleep periods as evidenced by ABP monitoring. Higher aldosterone levels were associated with higher DBP, but not systolic BP, in the clinic and during the awake and asleep periods. Further clinical investigation of novel and approved medications that target low renin physiology such as epithelial sodium channel inhibitors and mineralocorticoid receptor antagonists may be paramount in improving hypertension control in African Americans.

Little is known about the longitudinal association between fasting glucose (FG) and the diurnal cortisol profile among those with normal fasting glucose (NFG), impaired fasting glucose (IFG) and diabetes. To assess the temporality of the relationship between cortisol and glucose, we examined the association of: A) change (Δ) in diurnal cortisol curve features with ΔFG; B) prior annual percent change in FG with diurnal cortisol curve features; and C) baseline cortisol curve features with ΔFG over 6 years among participants with NFG, IFG and diabetes in the Multi-Ethnic Study of Atherosclerosis. The main outcome measures were: A) 6-year ΔFG (n = 512); B) diurnal cortisol curve features (wake-up cortisol levels, cortisol awakening response, total area under the curve, overall decline slope and bedtime cortisol) (n = 1275); and C) 6-year ΔFG (n = 700). After full multivariable adjustment among participants with diabetes, each annual percent change increase in wake-up cortisol, total area under the curve (AUC), and overall decline slope was associated with a significant increase in FG over 6 years in all models (all p < 0.05). A 1% prior annual increase in FG was associated with a 2.8 % lower (-2.8 %; 95 % CI: -5.3 % to -0.4 %) bedtime cortisol among participants with NFG at baseline. A 1 % flatter overall decline slope was associated with a 0.19 % increase in subsequent annual % change in FG over 6 years among participants with diabetes. Among participants with diabetes there was a positive association of change in wake-up cortisol, total AUC and overall decline slope with change in FG. Baseline overall decline slope was positively associated with change in FG among the baseline diabetes group. These results suggest a detrimental role of cortisol contributing to glycemia among individuals with diabetes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products. This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on α4β2-nAChRs occupancy, nicotine-induced change in [11C]raclopride non-displaceable binding potential (BPND), and behavioral measures of cigarette smoking, nicotine craving, and withdrawal., Methods: Current nicotine dependent daily smokers (N = 17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography), we characterized α4β2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal., Results: Varenicline compared with placebo resulted in significant reductions in [18F]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen, and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between α4β2-nAChRs BPND measured in thalamus during the [18F]AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum., Conclusion: This is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of α4β2-nAChRs and the magnitude of dopamine release following nicotine use., Implications: It has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4β2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Functional MRI (fMRI) task-related analyses rely on an estimate of the brain's hemodynamic response function (HRF) to model the brain's response to events. Although changes in the HRF have been found after acute alcohol administration, the effects of heavy chronic alcohol consumption on the HRF have not been explored, and the potential benefits or pitfalls of estimating each individual's HRF on fMRI analyses of chronic alcohol use disorder (AUD) are not known., Methods: Participants with AUD and controls (CTL) received structural, functional, and vascular scans. During fMRI, participants were cued to tap their fingers, and averaged responses were extracted from the motor cortex. Curve fitting on these HRFs modeled them as a difference between 2 gamma distributions, and the temporal occurrence of the main peak and undershoot of the HRF was computed from the mean of the first and second gamma distributions, respectively., Results: ANOVA and regression analyses found that the timing of the HRF undershoot increased significantly as a function of total lifetime drinking. Although gray matter volume in the motor cortex decreased with lifetime drinking, this was not sufficient to explain undershoot timing shifts, and vascular factors measured in the motor cortex did not differ among groups. Comparison of random-effects analyses using custom-fitted and canonical HRFs for CTL and AUD groups showed better results throughout the brain for custom-fitted versus canonical HRFs for CTL subjects. For AUD subjects, the same was true except for the basal ganglia., Conclusions: These findings suggest that excessive alcohol consumption is associated with changes in the HRF undershoot. HRF changes could provide a possible biomarker for the effects of lifetime drinking on brain function. Changes in HRF topography affect fMRI activation measures, and subject-specific HRFs generally improve fMRI activation results., (© 2020 by the Research Society on Alcoholism.)

Chronic exposure to cortisol is associated with cardiovascular, metabolic, and psychiatric disorders. Although cortisol can be readily measured from peripheral sources such as blood, urine, or saliva, multiple samplings spanning several days to weeks are necessary to reliably assess chronic cortisol exposure levels (referred to as cortisol load). Although cortisol levels in hair have been proposed as a measure of cortisol load, measurement is cumbersome and many people are not candidates due to short hair length and use of hair dyes. To date, there are no blood biomarkers that capture cortisol load. To identify a blood biomarker capable of integrating one-month cortisol exposure levels, 75 healthy participants provided 30+ days of awakening and bedtime saliva cortisol and completed psychosocial measures of anxiety, depression, and stress. Mean daily awakening and bedtime cortisol levels were then compared to CpG methylation levels, gene expression, and genotypes of the stress response gene FKBP5 obtained from blood drawn on the last day of the study. We found a correlation between FKBP5 methylation levels and mean 30+day awakening and bedtime cortisol levels (|r|≥0.32, p ≤ 0.006). We also observed a sex-specific correlation between bedtime cortisol levels and FKBP5 mRNA expression in female participants (r = 0.42, p = 0.005). Dividing the 30-day sampling period into four weekly bins showed that the correlations for both methylation and expression were not being driven by cortisol levels in the week preceding the blood draw. We also identified a female-specific association between FKBP5 mRNA expression and scores on the Beck Anxiety Inventory (r = 0.37, p = 0.013) and Beck Depression Inventory-II (r = 0.32, p = 0.033). Finally, DNA was genotyped at four SNPs, and variation in rs4713902 was shown to have an effect on FKBP5 expression under a codominant model (f = 3.41, p = 0.048) for females only. Our results suggest that blood FKBP5 DNA methylation and mRNA expression levels may be a useful marker for determining general or sex-specific 30-day cortisol load and justifies genome-wide approaches that can potentially identify additional cortisol markers with broader clinical utility., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As genomes of a wider variety of animals become available, there is an increasing need for tools that can capture dynamic epigenetic changes in these animal models. The rat is one particular model animal where an epigenetic tool can complement many pharmacological and behavioral studies to provide insightful mechanistic information. To this end, we adapted the SureSelect Target Capture System (referred to as Methyl-Seq) for the rat, which can assess DNA methylation levels across the rat genome. The rat design targeted promoters, CpG islands, island shores, and GC-rich regions from all RefSeq genes. To implement the platform on a rat experiment, male Sprague Dawley rats were exposed to chronic variable stress for 3 weeks, after which blood samples were collected for genomic DNA extraction. Methyl-Seq libraries were constructed from the rat DNA samples by shearing, adapter ligation, target enrichment, bisulfite conversion, and multiplexing. Libraries were sequenced on a next-generation sequencing platform and the sequenced reads were analyzed to identify DMRs between DNA of stressed and unstressed rats. Top candidate DMRs were independently validated by bisulfite pyrosequencing to confirm the robustness of the platform. Results demonstrate that the rat Methyl-Seq platform is a useful epigenetic tool that can capture methylation changes induced by exposure to stress.

Women and men differ in their risk for developing stress-related conditions such as alcohol use and anxiety disorders and there are gender differences in the typical sequence in which these disorders co-occur. However, the neural systems underlying these gender-biased psychopathologies and clinical course modifiers in humans are poorly understood and may involve both central and peripheral mechanisms regulating the limbic-hypothalamic-pituitary-adrenal axis. In the present randomized, double blind, placebo-controlled, triple-dummy crossover study, we juxtaposed a centrally-acting, citalopram (2 mg/unit BMI) neuroendocrine stimulation test with a peripherally-acting, dexamethasone (Dex) (1.5 mg)/corticotropin-releasing factor (CRF) (1 μg/kg) test in euthymic women (N = 38) and men (N = 44) with (54%) and without histories of alcohol dependence to determine whether sex, alcohol dependence or both influenced the adrenocorticotropic hormone (ACTH) and cortisol responses to the pharmacological challenges and to identify the loci of these effects. We found that central serotonergic mechanisms, along with differences in pituitary and adrenal sensitivity, mediated sexually-diergic ACTH and cortisol responses in a stressor-specific manner regardless of a personal history of alcohol dependence. Specifically, women exhibited a greater response to the Dex/CRF test than they did the citalopram test while men exhibited the opposite pattern of results. Women also had more robust ACTH, cortisol and body temperature responses to Dex/CRF than men, and exhibited a shift in their adrenal glands' sensitivity to ACTH as measured by the cortisol/log (ACTH) ratio during that session in contrast to the other test days. Our findings indicate that central serotonergic and peripheral mechanisms both play roles in mediating sexually dimorphic, stressor-specific endocrine responses in humans regardless of alcohol dependence history., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Subclinical hypercortisolism and hypothalamic-pituitary-adrenal (HPA) axis dysfunction are associated with type 2 diabetes (T2DM), cardiovascular disease, and metabolic dysfunction. Intronic methylation of FKBP5 has been implicated as a potential indicator of chronic cortisol exposure. Our overall objective in this study was to determine the association of chronic cortisol exposure, measured via percent methylation of FKBP5 at intron 2, with percent glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-cholesterol), waist circumference (WC), and body mass index (BMI), in a clinic-based sample of 43 individuals with T2DM., Results: Greater percent methylation of the FKBP5 intron 2 at one CpG-dinucleotide region was significantly associated with higher HbA1c ( β  = 0.535, p  = 0.003) and LDL cholesterol ( β  = 0.344, p  = 0.037) and a second CpG-dinucleotide region was significantly associated with higher BMI and WC ( β  = 0.516, p  = 0.001; β  = 0.403, p  = 0.006, respectively)., Conclusions: FKBP5 methylation may be a marker of higher metabolic risk in T2DM, possibly secondary to higher exposure to cortisol. Further work should aim to assess the longitudinal association of FKBP5 with cardiovascular disease and glycemic outcomes in T2DM as a first step in understanding potential preventive and treatment-related interventions targeting the HPA axis., Competing Interests: Patients who were willing to participate provided written informed consent. This study was approved by the Johns Hopkins University School of Medicine Institutional Review Board.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Although epidemiological research has shown an increase in drinking following stressors and trauma, limited paradigms have been validated to study the relationship between stress and drinking in the human laboratory. The current study developed a progressive ratio (PR) operant procedure to examine the effects of psychosocial stress on alcohol craving and several alcohol-motivated behaviors in persons with alcohol use disorder. Current heavy, nontreatment-seeking drinkers (N = 30) were media-recruited and completed a comprehensive assessment of recent drinking, mood and health. Participants were admitted to the clinical research unit and underwent 4-day, physician-monitored alcohol abstinence. On days 4 and 5, participants underwent the Trier Social Stress Test or a neutral session in random order followed by the alcohol-motivated response (AMR) procedure in which subjects worked for money or alcohol under a PR operant procedure. Subjects received earned money vouchers or alcohol at the conclusion of the session. The Trier Social Stress Test increased alcohol craving and rate of responding and decreased the number of changeovers between alcohol versus money reinforcers on the PR schedule. There was a positive relationship between alcohol craving and drinks earned during the stress session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, thereby setting the stage for future studies of alcohol interventions., (© 2017 The Authors.Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

There is increasing awareness of the potential negative impacts of participant deception on research, including possibly undermining reliability and reproducibility of study findings. These deceptive individuals set their personal interests above the rules of study participation, thereby jeopardizing data quality as well as placing themselves and others at risk. The costs of participant deception are numerous. Overall, it reduces statistical power and may even result in false conclusions about efficacy and safety. To date, most studies have not utilized sufficient methods to detect rule-breaking subjects. The purpose of this article is to bring to the attention of alcohol and other drug researchers issues involving deceptive participants. The review will suggest alcohol-specific as well as more general strategies to identify and thereby minimize enrollment of these deceptive participants. Specifically, we will identify strategies that are employed in different phases of human alcohol research and advance approaches that may be helpful to the field in reducing these contaminants. As a field, we need to be more proactive in identifying the deceptive participant even at the cost of more burdensome study enrollment. In light of the systemic nature and multipronged damage that this emerging pattern of deception inflicts on clinical research, it is imperative that we each assume greater responsibility for our role in mitigating this source of research contamination., (Copyright © 2017 by the Research Society on Alcoholism.)

During the critical developmental periods of childhood when neural plasticity is high, exposure to early life stress (ELS) or trauma may lead to enduring changes in physiological stress systems and enhanced vulnerability for psychopathological conditions such as post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) in adulthood. Clinical and preclinical studies have sought to understand the possible mechanisms linking ELS, PTSD, and AUD. Preclinical studies have employed animal models of stress to recapitulate PTSD-like behavioral deficits and alcohol dependence, providing a basic framework for identifying common physiological mechanisms that may underlie these disorders. Clinical studies have documented ELS-related endocrine dysregulation and genetic variations associated with PTSD and AUD, as well as disruption in crucial neural circuitry throughout the corticomesolimbic region. Despite limitations and challenges, both types of studies have implicated three interrelated mechanisms: hypothalamic pituitary adrenal (HPA) axis and glucocorticoid signaling dysregulation, genetics, and epigenetics. ELS exposure leads to disruption of HPA axis function and glucocorticoid signaling, both of which affect homeostatic cortisol levels. However, individual response to ELS depends on genetic variations at specific genes that moderate HPA axis and brain function, thus influencing susceptibility or resilience to psychopathologies. Epigenetic-influenced pathways also are emerging as a powerful force in helping to create the PTSD and AUD phenotypes. Dysregulation of the HPA axis has an epigenetic effect on genes that regulate the HPA axis itself, as well as on brain-specific processes such as neurodevelopment and neurotransmitter regulation. These studies are only beginning to elucidate the underpinnings of ELS, PTSD, and AUD. Larger human cohorts, identification of additional genetic determinants, and better animal models capable of recapitulating the symptoms of PTSD and AUD are needed., Competing Interests: Financial Disclosure The authors declare that they have no competing financial interests.

Objectives: This study examined the association of aldosterone and plasma renin activity (PRA) with incident cardiovascular disease (CVD), using a composite endpoint of coronary heart disease, stroke, and/or heart failure and mortality among African Americans in the Jackson Heart Study., Background: There is a paucity of data for the association of aldosterone and PRA with incident CVD or all-cause mortality among community-dwelling African Americans., Methods: A total of 4,985 African American adults, 21 to 94 years of age, were followed for 12 years. Aldosterone, PRA, and cardiovascular risk factors were collected at baseline (from 2000 to 2004). Incident events included coronary heart disease and stroke (assessed from 2000 to 2011) and heart failure (assessed from 2005 to 2011). Cox models were used to estimate hazard ratios (HRs) for incident CVD and mortality, adjusting for age, sex, education, occupation, current smoking, physical activity, dietary intake, and body mass index., Results: Among 4,160 participants without prevalent CVD over a median follow-up of 7 years, there were 322 incident CVD cases. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HR of 1.26 (95% confidence intervals [CI]: 1.14 to 1.40) and 1.16 (95% CI: 1.02 to 1.33) for incident CVD, respectively. Over a median of 8 years, 513 deaths occurred among 4,985 participants. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HRs of 1.13 (95% CI: 1.04 to 1.23) and 1.12 (95% CI: 1.01 to 1.24) for mortality, respectively., Conclusions: Elevated aldosterone and PRA may play a significant role in the development of CVD and all-cause mortality among African Americans., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the association between perceived stress and subsequent alcohol use in women living with HIV., Methods: Women (n=338) receiving HIV care between April 2006 and July 2010 who enrolled in either a brief intervention for hazardous drinking or a cohort of non-hazardous drinkers completed a 90-day drinking and drug use history, and completed stress, depression and anxiety measures at 0, 6, and 12 months. We examined the association between perceived stress at months 0 or 6 and measures of quantity and frequency of alcohol use in months 3-6 and 9-12, respectively., Results: The association between perceived stress and subsequent alcohol use depended on whether women were heavy or moderate drinkers at index visit. Among women reporting ≥7 drinks/week at index visit, high levels of perceived stress were associated with subsequent increased alcohol intake. However, among women reporting >0 but <7 drinks/week at index visit, high levels of perceived stress were associated with a subsequent reduction in drinking., Conclusions: Baseline drinking status moderates the relationship between perceived stress and subsequent alcohol use. Perceived stress is an important therapeutic target in women who are heavy drinkers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The current study examined independent and interactive effects of polymorphisms of the mu opioid receptor gene (OPRM1, A118G) and variable number tandem repeats of the dopamine transporter gene (DAT1, SLC6A3) on alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers., Methods: Participants completed an in-person assessment, which included self-reported alcohol drinking patterns and blood sampling for DNA, and in a second visit, a cumulative alcohol dosing procedure with subjective ratings across multiple time points and breath alcohol contents (0.03 to 0.1%). DNA was analyzed for OPRM1 AA versus AG/GG (*G) genotypes, DAT1 10-repeat allele (A10) versus 9 or lesser alleles (A9), and ancestral informative markers., Results: There were significant epistatic interactions between OPRM1 and DAT1 genotypes. Subjective High Assessment Scale scores after alcohol consumption were highest in *G and A9 carriers, and lowest in *G and A10 carriers. Negative subjective effects were also highest in *G and A9 carriers. Effects were similar in a sensitivity analysis limited to Caucasian subjects. There were independent and epistatic interactions on drinking. The OPRM1 *G allele was independently associated with fewer heavy drinking days. The A9 allele was associated with a greater number of drinking days, which was attenuated in carriers of the *G allele., Conclusions: These findings highlight the biological importance of interactions between these 2 genes and interactions between brain opioid and dopamine systems., (Copyright © 2017 by the Research Society on Alcoholism.)

Background: Stress and anxiety are widely considered to be causally related to alcohol craving and consumption, as well as development and maintenance of alcohol use disorder (AUD). However, numerous preclinical and human studies examining effects of stress or anxiety on alcohol use and alcohol-related problems have been equivocal. This study examined relationships between scores on self-report anxiety, anxiety sensitivity, and stress measures and frequency and intensity of recent drinking, alcohol craving during early withdrawal, as well as laboratory measures of alcohol craving and stress reactivity among heavy drinkers with AUD., Methods: Media-recruited, heavy drinkers with AUD (N = 87) were assessed for recent alcohol consumption. Anxiety and stress levels were characterized using paper-and-pencil measures, including the Beck Anxiety Inventory (BAI), the Anxiety Sensitivity Index-3 (ASI-3), and the Perceived Stress Scale (PSS). Eligible subjects (N = 30) underwent alcohol abstinence on the Clinical Research Unit; twice daily measures of alcohol craving were collected. On day 4, subjects participated in the Trier Social Stress Test; measures of cortisol and alcohol craving were collected., Results: In multivariate analyses, higher BAI scores were associated with lower drinking frequency and reduced drinks/drinking day; in contrast, higher ASI-3 scores were associated with higher drinking frequency. BAI anxiety symptom and ASI-3 scores also were positively related to Alcohol Use Disorders Identification Test total scores and AUD symptom and problem subscale measures. Higher BAI and ASI-3 scores but not PSS scores were related to greater self-reported alcohol craving during early alcohol abstinence. Finally, BAI scores were positively related to laboratory stress-induced cortisol and alcohol craving. In contrast, the PSS showed no relationship with most measures of alcohol craving or stress reactivity., Conclusions: Overall, clinically oriented measures of anxiety compared with perceived stress were more strongly associated with a variety of alcohol-related measures in current heavy drinkers with AUD., (Copyright © 2017 The Authors. Alcoholism: Clinical and Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism.)

The aim of this study was to examine the relationship between family history of alcohol use disorder and striatal dopamine using positron emission tomography imaging. Participants were 84 healthy, 18- to 30-year-old, social drinkers recruited via fliers and newspaper advertisements. At assessment, participants completed measures of lifetime personal and family substance use and psychiatric symptoms. Participants underwent two consecutive positron emission tomography scans using the D 2 /D 3 dopamine receptor radioligand [ 11 C]raclopride. Scans were preceded by intravenous saline and amphetamine 0.3 mg/kg, providing measures of baseline [ 11 C]raclopride binding potential (BP ND ) and change in [ 11 C]raclopride (ΔBP ND ). Subjective ratings of stimulant drug effects were collected during scans. Subjects were classified as family history positive (FHP) if they reported any first-degree relative with alcohol use disorder (AUD) and family history negative (FHN) if no first-degree relatives had history of AUD. Participants were predominantly White (69.0 percent) and male (62.1 percent). Baseline [ 11 C]raclopride BP ND was generally higher in FHP compared with FHN subjects across striatal subdivisions. There were no differences in ΔBP ND across regions. Negative subjective drug effects were more pronounced in FHP than in FHN subjects. While FHN subjects evidenced the expected positive relationship between ΔBP ND and positive subjective drug effects, this relationship was disrupted in FHP subjects. There are key differences in dopamine status and subjective stimulant drug experiences as a function of family AUD history. These findings have important implications for understanding risk for AUD development in FHP offspring., Competing Interests: Drs. Alvanzo, Kuwabara, McCaul, and Xu reported no biomedical financial interests or potential conflicts of interest., (© 2015 Society for the Study of Addiction.)

Objective: To estimate the crude prevalence of minor depressive disorder (MinD) in a clinic-based population of adults with type 2 diabetes., Methods: We screened a clinical sample of 702 adults with type 2 diabetes for depressive symptoms using the Patient Health Questionnaire-2 and performed a structured diagnostic psychiatric interview on 52 screen-positive and a convenience sample of 51 screen-negative individuals. Depressive disorder diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) Text Revised criteria and categorized as MinD, major depressive disorder (MDD), or no depressive disorder. We estimated prevalence of MinD and MDD and derived 95% CIs., Results: The crude prevalence of current, past, and current or past MinD was 4.3% (95% CI: 0.9-9.2%), 9.6% (95% CI: 3.9-15.9%), and 13.9% (95% CI: 7.7-21.2%), respectively. The crude prevalence of current, past, and current or past MDD was slightly higher-5.0% (95% CI: 1.9-9.4%), 12.0% (95% CI: 6.1-19.5%), and 17.0% (95% CI: 10.1-24.8%), respectively. There was a high prevalence of coexisting anxiety disorders in individuals with MinD (42.2%) and MDD (8.1%). Hemoglobin A1c levels were not significantly different in individuals with MinD or MDD compared to those without a depressive disorder., Conclusions: MinD is comparably prevalent to MDD in patients with type 2 diabetes; both disorders are associated with concomitant anxiety disorders. MinD is not included in the DSM-5; however, our data support continuing to examine patients with chronic medical conditions for MinD., (Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The transition from microscopic to fully endoscopic transsphenoidal surgery requires a surgeon to assess how the change in technique will affect the extent of tumor resection (EOR), outcomes, and complications. We compared a single surgeon's experience transitioning from one technique to the other and examined the operative outcomes and EOR between microscopic versus endoscopic transsphenoidal surgery., Methods: Retrospective data analysis of adult patients who were treated surgically for a pituitary adenoma between August 2005 and May 2015 by a single neurosurgeon, who was originally trained and practiced in the microscopic transsphenoidal approach. Patient demographics, perioperative conditions, tumor characteristics, operative times, volumetric EOR, postoperative outcome, and the endoscopic learning curve were evaluated., Results: One hundred and nine patients underwent microscopic transsphenoidal surgery and 275 patients underwent a fully endoscopic approach. The patient characteristics were similar in the 2 groups. Operative room time was significantly shorter in the endoscopic group than in the microscopic group (180.2 vs. 215.6 minutes; P < 0.001). The endoscopic and microscopic groups had similar volumetric EOR (85.1% vs. 82.8%; P = 0.371) as well as residual tumor volume (1.06 cm 3 vs. 1.15 cm 3 ; P = 0.765). The mean length of hospital stay was 2.4 days in the endoscopic group and 3.2 days in the microscopic group (P = 0.03)., Conclusions: During the transition from the microscopic to the endoscopic approach, similar surgical outcomes and EOR were achieved in the 2 cohorts. In our experience, the endoscopic approach offers the advantage of shorter operative times and lengths of hospital stays after the surgeon has developed more experience with the technique., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS., Methods: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus., Results: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity)., Conclusion: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH., Abbreviations: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotrophin-releasing hormone CS = Cushing syndrome DDAVP = desmopressin EAS = ectopic ACTH secretion IJVS = internal jugular vein sampling IPSS = inferior petrosal sinus sampling JVS = jugular venous sampling MRI = magnetic resonance imaging.

Cross-sectional association has been shown between type 2 diabetes and hypothalamic-pituitary-adrenal (HPA) axis dysregulation; however, the temporality of this association is unknown. Our aim was to determine if type 2 diabetes is associated with longitudinal change in daily cortisol curve features. We hypothesized that the presence of type 2 diabetes may lead to a more blunted and abnormal HPA axis profile over time, suggestive of increased HPA axis dysregulation. This was a longitudinal cohort study, including 580 community-dwelling individuals (mean age 63.7 ± 9.1 years; 52.8 % women) with (n = 90) and without (n = 490) type 2 diabetes who attended two MultiEthnic Study of Atherosclerosis Stress ancillary study exams separated by 6 years. Outcome measures that were collected were wake-up and bedtime cortisol, cortisol awakening response (CAR), total area under the curve (AUC), and early, late, and overall decline slopes. In univariate analyses, wake-up and AUC increased over 6 years more in persons with as compared to those without type 2 diabetes (11 vs. 7 % increase for wake-up and 17 vs. 11 % for AUC). The early decline slope became flatter over time with a greater flattening observed in diabetic compared to non-diabetic individuals (23 vs. 9 % flatter); however, the change was only statistically significant for wake-up cortisol (p-value: 0.03). Over time, while CAR was reduced more, late decline and overall decline became flatter, and bedtime cortisol increased less in those with as compared to those without type 2 diabetes, none of these changes were statistically significant in adjusted models. We did not identify any statistically significant change in cortisol curve features over 6 years by type 2 diabetes status.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the TSST than do women during the follicular phase of the menstrual cycle., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Previous research has suggested that activation of the renin-angiotensin-aldosterone system may promote insulin resistance and β-cell dysfunction, but the association with incident diabetes in African Americans is unknown., Objective: We examined the association of aldosterone and renin with insulin resistance, β-cell function, and incident diabetes in a large African American cohort., Design: The Jackson Heart Study is a prospective study of the development and progression of cardiovascular disease in African Americans., Setting: Participants were recruited from the tricounty area of metropolitan Jackson, Mississippi., Participants: A total of 5301 African American adults, aged 21–94 years, were assessed at baseline and through 12 years of follow-up. Data on aldosterone, renin, and risk factors were collected at baseline (2000–2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at baseline and through 12 years of follow-up. Participants were excluded for missing data on baseline covariates or diabetes follow-up. Cox regression was used to estimate hazard ratios (HR) for incident diabetes using sequential modeling adjusting for age, sex, education, occupation, systolic blood pressure, current smoking, physical activity, dietary intake, and body mass index., Exposures: Aldosterone, renin, and diabetes risk factors were measured., Outcome: Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and incident diabetes., Results: Among 3234 participants over a median of 8.0 years of follow-up, there were 554 cases of incident diabetes. Every 1% increase in log-transformed aldosterone was associated with a 0.18% higher log-transformed HOMA-IR in cross-sectional analyses of nondiabetic participants (P < .001). Log-transformed aldosterone and renin levels in the fifth vs first quintile were associated with a 78% (HR 1.78, 95% confidence interval 1.35–2.34) and 35% (HR 1.35, 95% confidence interval 1.06–1.72) increase in diabetes risk, respectively, in fully adjusted models., Conclusions: Activation of the renin-angiotensin-aldosterone system may play a significant role in the development of insulin resistance and diabetes in African Americans.

Evidence of the link between job strain and cortisol levels has been inconsistent. This could be due to failure to account for cortisol variability leading to underestimated standard errors. Our objective was to model the relationship between job strain and the whole cortisol curve, accounting for sources of cortisol variability. Our functional mixed-model approach incorporated all available data-18 samples over 3 days-and uncertainty in estimated relationships. We used employed participants from the Multi-Ethnic Study of Atherosclerosis Stress I Study and data collected between 2002 and 2006. We used propensity score matching on an extensive set of variables to control for sources of confounding. We found that job strain was associated with lower salivary cortisol levels and lower total area under the curve. We found no relationship between job strain and the cortisol awakening response. Our findings differed from those of several previous studies. It is plausible that our results were unique to middle- to older-aged racially, ethnically, and occupationally diverse adults and were therefore not inconsistent with previous research among younger, mostly white samples. However, it is also plausible that previous findings were influenced by residual confounding and failure to propagate uncertainty (i.e., account for the multiple sources of variability) in estimating cortisol features., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this paper, we address issues raised by Tierney and Hart (Assessing Complex Cognitive Functioning Requires Multiple Tasks) in response to our recently published findings showing that less advantageous decision-making on the Iowa Gambling Task (IGT) was associated with enhanced right ventral striatal dopamine response to intravenous amphetamine (Oswald et al., 2015). We agree with the overall premise of the paper, which was that decision-making involves multiple components, which may not be tapped by a single measure. While Tierney and Hart also bring up some important issues related to the construct validity of the IGT, we suggest that they are failing to put the findings within the context of the growing body of research that has highlighted the role of DA function in risk-taking behavior across species using a variety of tasks. It should also be noted that it was not our goal to "cover all bases" within the context of a single study. Nevertheless, we appreciate the discussion, which we believe highlights the need for further empirical refinement of the construct to facilitate detection and understanding of the differential role that specific molecular mechanisms may play in the component processes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Copeptin levels are elevated in severe medical conditions, an effect that is attributed to elevated arginine vasopressin (AVP) levels in response to physiological stress, resulting in activation of hypothalamus-pituitary-adrenal (HPA) axis. In the current study, we wanted to determine if copeptin is responsive to psychological stress, correlates with cortisol and adrenocorticotropin hormone (ACTH), and if associations differed by sex., Materials and Methods: In a cross-sectional study that included 100 healthy men (41%) and women (59%) (aged 18-30 years; mean 24.6 ± 3 years), who underwent the Trier Social Stress Test (TSST), we examined the association between percent change (peak-baseline/baseline) in copeptin levels and percent change in log ACTH and cortisol. Three baselines samples were drawn followed by blood sampling at 20, 35, 50, 65 and 85 min after TSST., Results: There was a significant positive association between the percent change in copeptin and the percent change in log-transformed salivary cortisol (β-coefficient=0.95; p=0.02). The association between percent change in copeptin and log-transformed serum cortisol was not statistically significant in the overall population. There was a trend for a non-significant association between percent change in copeptin and percent change in log-transformed ACTH (β-coefficient=1.14; p=0.06). In males, there was a significant positive association between the percent change in copeptin levels and log-transformed salivary (β-coefficient=1.33, p=0.016) and serum cortisol (β-coefficient=0.69, p=0.01), whereas in women there was no statistically significant association., Conclusions: We found a significant positive association between percent change in copeptin and percent change in salivary and serum cortisol among males only., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Recent functional magnetic resonance imaging (fMRI) studies have provided compelling evidence that corticolimbic brain regions are integrally involved in human decision-making. Although much less is known about molecular mechanisms, there is growing evidence that the mesolimbic dopamine (DA) neurotransmitter system may be an important neural substrate. Thus far, direct examination of DA signaling in human risk-taking has centered on gambling disorder. Findings from several positron emission tomography (PET) studies suggest that dysfunctions in mesolimbic DA circuits may play an important role in gambling behavior. Nevertheless, interpretation of these findings is currently hampered by a need for better understanding of how individual differences in regional DA function influence normative decision-making in humans. To further our understanding of these processes, we used [(11)C]raclopride PET to examine associations between ventral striatal (VS) DA responses to amphetamine (AMPH) and risky decision-making in a sample of healthy young adults with no history of psychiatric disorder, Forty-five male and female subjects, ages 18-29 years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second, by intravenous AMPH (0.3mg/kg). Findings of primary analyses showed that less advantageous decision-making was associated with greater right VS DA release; the relationship did not differ as a function of gender. No associations were observed between risk-taking and left VS DA release or baseline D2/D3 receptor availability in either hemisphere. Overall, the results support notions that variability in striatal DA function may mediate inter-individual differences in risky decision-making in healthy adults, further suggesting that hypersensitive DA circuits may represent a risk pathway in this population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Stimuli paired with alcohol may evoke conditioned responses that influence consumption and relapse. Understanding extinction of conditioned responses for both alcohol and nonalcoholic reinforcers, and their relation to subsequent consumption, may be useful in identifying methods to maintain abstinence., Methods: Nine baboons self-administered alcohol (n = 4) or a nonalcoholic reinforcer (orange-flavored Tang(®) , n = 5) under a 3-component chained schedule of reinforcement (CSR). Each component was associated with distinct stimuli and response requirements, which modeled periods of anticipation (Component 1), seeking (Component 2), and consumption (Component 3). No behavioral contingencies were in effect during Component 1. Responses in Component 2, required to gain access to Component 3, provided indices of seeking behavior. Alcohol or Tang® was available only in Component 3. Initial conditions parametrically manipulated the concentration of alcohol (2 to 6% w/v) or Tang (25 to 100%) that was available for self-administration. The breaking point (BP) of alcohol- and Tang-seeking responses at each of the concentrations was determined by adding a progressive ratio schedule to Component 2. Extinction of responding under stimulus conditions identical to those during baseline, but with no access to alcohol or Tang, was examined using across- and within-session extinction procedures., Results: The BP for 2% w/v alcohol was lower than that for 4 and 6%, which were closely similar. For Tang, BPs increased as the concentration increased. When concentrations of alcohol and Tang were adjusted to produce comparable BPs, self-administration of Tang was higher when compared to alcohol; however, alcohol-related cues maintained higher BPs than Tang-related cues when only water was available for self-administration. Alcohol seeking and self-administration responses were more resistant to extinction than those for Tang., Conclusions: Stimuli paired with alcohol or nonalcoholic reinforcers will gain different motivational properties. Alcohol-related stimuli produced persistent responding that was highly resistant to change, highlighting the role of environmental stimuli in compulsive drinking and relapse., (Copyright © 2014 by the Research Society on Alcoholism.)

Purpose: According to Pituitary and Endocrine Society recommendations, cabergoline (CAB) therapy can be discontinued after 2 years in hyperprolactinemic patients who fit certain criteria. Previous studies found recurrence rates ranging between 26 and 69 %. Whether CAB therapy can be successfully discontinued after one unsuccessful withdrawal is unknown., Methods: We conducted a pilot prospective two-center study on a second attempt of CAB withdrawal. Inclusion criteria were: (1) recurrence of hyperprolactinemia after first withdrawal; (2) additional CAB therapy for at least 2 years; (3) normal serum prolactin; (4) CAB dose ≤ 1 mg/week. Prolactin level was monitored after discontinuing therapy. Median follow up for patients who are still in remission was 42 months (range = 24-60)., Results: A total of 17 patients were recruited. Mean age was 41.0 ± 17.3 years. 65 % were female. Initial tumors were microadenoma in 64.7 %, and macroadenoma in 35.3 %. The average weekly CAB dose at second withdrawal was 0.38 ± 0.20 mg (median = 0.25, range = 0.175-1). Eleven of 17 patients (64.7 %) recurred. Median time to recurrence was 6 months. The incidence of recurrence was 44 events per 100 person-years. The estimated cumulative hazard of recurrence was 40 and 82 % at 6 and 12 months respectively. The probability to be recurrence-free at 6 and 12 months was 65 and 41 %, respectively., Conclusions: Second attempt of CAB withdrawal after 2 additional years of therapy may be successful in some patients. A second withdrawal can be attempted with close monitoring of prolactin level. In this study, we could not identify any predictor of recurrence. Most of the recurrences occurred within the first 12 months after withdrawal.

Persons with a history of alcohol dependence are more likely to use tobacco and to meet criteria for nicotine dependence compared with social drinkers or non-drinkers. The high levels of comorbidity of nicotine and alcohol use and dependence are thought to be related to interactions between nicotinic, opioid and dopamine receptors in mesolimbic regions. The current study examined whether individual differences in regional μ-opioid receptor (MOR) availability were associated with tobacco use, nicotine dependence and level of nicotine craving in 25 alcohol-dependent (AD) subjects. AD subjects completed an inpatient protocol, which included medically supervised alcohol withdrawal, monitored alcohol abstinence, transdermal nicotine maintenance (21 mg/day) and Positron Emission Tomography (PET) imaging using the MOR agonist [(11) C]-carfentanil (CFN) before (basal scan) and during treatment with 50 mg/day naltrexone (naltrexone scan). Subjects who had higher scores on the Fagerström Nicotine Dependence Test had significantly lower basal scan binding potential (BPND ) across mesolimbic regions, including the amygdala, cingulate, globus pallidus, thalamus and insula. Likewise, the number of cigarettes per day was negatively associated with basal scan BPND in mesolimbic regions. Higher nicotine craving was significantly associated with lower BPND in amygdala, globus pallidus, putamen, thalamus and ventral striatum. Although blunted during naltrexone treatment, the negative association was maintained for nicotine dependence and cigarettes per day, but not for nicotine craving. These findings suggest that intensity of cigarette smoking and severity of nicotine dependence symptoms are systematically related to reduced BPND across multiple brain regions in AD subjects., (© 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.)

Rationale: Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear., Objectives: This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans., Methods: Following intake assessment, 28 healthy male and female adults, aged 18-29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg)., Results: Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress., Conclusions: Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.

Background: Epigenetic studies that utilize peripheral tissues to identify molecular substrates of neuropsychiatric disorders rely on the assumption that disease-relevant, cellular alterations that occur in the brain are mirrored and detectable in peripheral tissues such as blood. We sought to test this assumption by using a mouse model of Cushing's disease and asking whether epigenetic changes induced by glucocorticoids can be correlated between these tissue types., Methods: Mice were treated with different doses of glucocorticoids in their drinking water for four weeks to assess gene expression and DNA methylation (DNAm) changes in the stress response gene Fkbp5., Results: Significant linear relationships were observed between DNAm and four-week mean plasma corticosterone levels for both blood (R(2)=0.68, P=7.1×10(-10)) and brain (R(2)=0.33, P=0.001). Further, degree of methylation change in blood correlated significantly with both methylation (R(2)=0.49, P=2.7×10(-5)) and expression (R(2)=0.43, P=3.5×10(-5)) changes in hippocampus, with the notable observation that methylation changes occurred at different intronic regions between blood and brain tissues., Conclusion: Although our findings are limited to several intronic CpGs in a single gene, our results demonstrate that DNA from blood can be used to assess dynamic, glucocorticoid-induced changes occurring in the brain. However, for such correlation analyses to be effective, tissue-specific locations of these epigenetic changes may need to be considered when investigating brain-relevant changes in peripheral tissues., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Context: Pituitary antibodies have been measured mainly to identify patients whose disease is caused or sustained by pituitary-specific autoimmunity. Although reported in over 100 publications, they have yielded variable results and are thus considered of limited clinical utility., Objectives: Our objectives were to analyze all publications reporting pituitary antibodies by immunofluorescence for detecting the major sources of variability, to experimentally test these sources and devise an optimized immunofluorescence protocol, and to assess prevalence and significance of pituitary antibodies in patients with pituitary diseases. STUDY DESIGN AND OUTCOME MEASURES: We first evaluated the effect of pituitary gland species, section fixation, autofluorescence quenching, blockade of unwanted antibody binding, and use of purified IgG on the performance of this antibody assay. We then measured cross-sectionally the prevalence of pituitary antibodies in 390 pituitary cases and 60 healthy controls, expressing results as present or absent and according to the (granular, diffuse, perinuclear, or mixed) staining pattern., Results: Human pituitary was the best substrate to detect pituitary antibodies and yielded an optimal signal-to-noise ratio when treated with Sudan black B to reduce autofluorescence. Pituitary antibodies were more common in cases (95 of 390, 24%) than controls (3 of 60, 5%, P = .001) but did not discriminate among pituitary diseases when reported dichotomously. However, when expressed according to their cytosolic staining, a granular pattern was highly predictive of pituitary autoimmunity (P < .0001)., Conclusion: We report a comprehensive study of pituitary antibodies by immunofluorescence and provide a method and an interpretation scheme that should be useful for identifying and monitoring patients with pituitary autoimmunity.

The association between neighborhood conditions and cortisol is rarely studied in children or adolescents and has been hampered by small sample size and racial/ethnic and geographic homogeneity. Our objective was to estimate the association between neighborhood disadvantage and salivary cortisol levels in a large, geographically and racially/ethnically diverse sample of adolescents from the National Comorbidity Survey Replication Adolescent Supplement. Salivary cortisol was collected before and after an interview administered in the adolescent's home. We used a propensity score approach to match adolescents living in disadvantaged neighborhoods with those in non-disadvantaged neighborhoods to create two similar groups based on the time and day of cortisol collection as well as demographic characteristics. Adolescents living in disadvantaged neighborhoods had higher pre-interview cortisol levels and steeper rates of decline in cortisol levels over the course of the interview than similar adolescents in non-disadvantaged neighborhoods. This bolsters the evidence base suggesting that place may influence the stress response system., (© 2013 Elsevier Ltd. All rights reserved.)

Cumulative cortisol burden is known to influence neuropsychiatric and metabolic disorders. To better understand the relationship between daily cortisol exposure and measures of the diurnal circadian cortisol rhythm, we examined the cross-sectional association of the cortisol awakening response (CAR) with wake-up cortisol, bedtime cortisol, diurnal slope, and total cortisol area under the curve (AUC). Up to 18 salivary cortisol samples were collected over 3 days from 935 White, Hispanic, and Black individuals (mean age 65 ± 9.8 years) in the Multi-Ethnic Study of Atherosclerosis. Outcome measures included awakening cortisol, CAR (awakening to 30 min post-awakening), early decline (30 min to 2h post-awakening), late decline (2h post-awakening to bedtime), and the corresponding AUCs. Total cortisol AUC was a summary measure of cumulative cortisol exposure. Higher CAR was associated with significantly lower wake-up cortisol (β=-0.56; 95% CI: -0.59 to -0.53) and a higher early decline AUC (β=0.38; 95% CI: 0.34-0.42) but was not associated with total cortisol AUC (β=0.04; 95% CI: -0.01 to 0.09), or other diurnal cortisol curve components following multivariable adjustment. Total cortisol AUC was significantly and positively associated with wake-up cortisol (β=0.36; 95% CI: 0.32-0.40), bedtime cortisol (β=0.61; 95% CI: 0.58-0.64), and other AUC measures, following multivariable adjustment. Associations were similar by sex, race/ethnicity, and age categories. We conclude that bedtime cortisol showed the strongest correlation with total cortisol AUC, suggesting it may be a marker of daily cortisol exposure., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Scientists have known for decades that persons who volunteer for behavioral research may be different from those who decline participation and that characteristics differentiating volunteers from non-volunteers may vary depending on the nature of the research. There is evidence that volunteer self-selection can impact representativeness of samples in studies involving physically or psychologically stressful procedures, such as electric shocks, sensory isolation, or drug effects. However, the degree to which self-selection influences sample characteristics in "stressful" studies involving positron emission tomography (PET) has not been evaluated. Since estimation of population parameters, robustness of findings, and validity of inferred relationships can all be impacted by volunteer bias, it is important to determine if self-selection may act as an unrecognized confound in such studies. In the present investigation, we obtained baseline data on 114 (56M, 58F) subjects who participated in a study involving completion of several self-report questionnaires and behavioral performance tasks. Participants were later given the opportunity to enroll in an [11C]raclopride PET study involving intravenous amphetamine (AMPH) administration. Demographic characteristics, personality traits, and task performance of subjects who consented to the latter study were compared with those who declined participation. Findings showed that the principal personality trait that distinguished the two groups was sensation-seeking; volunteers scored significantly higher on this dimension than non-volunteers. Males were more likely to volunteer than females. However, results of mediation analysis suggested that the relationship between gender and volunteer status was mediated by greater sensation-seeking traits in the males. Implications of these findings are discussed.

Rationale: Chronic dysregulation of hypothalamus-pituitary-adrenal (HPA) axis activity is related to several neuropsychiatric disorders. Studies suggest that cortisol response to stress has a strong genetic etiology, and that FK506 binding protein 5 (FKBP5) and G-protein coupled type-I CRH receptor (CRHR1) are key proteins regulating response. Variations in the genes encoding these proteins, FKBP5 and CRHR1, have been associated with several neuropsychiatric disorders., Objectives: We examined variation in these genes in relation to cortisol response to psychological stress in one of the largest Trier Social Stress Test (TSST) cohorts yet examined., Methods: A total of 368 healthy, young adults underwent the TSST. Salivary cortisol was measured at multiple time points before and after the stressor. Nine variants in FKBP5 and four in CRHR1 were assessed. Single marker analyses were conducted. Secondary analyses assessed haplotypes and interaction with stress-related variables., Results: The strongest association was for rs4713902 in FKBP5 with baseline cortisol (p dom = 0.0004). We also identified a male-specific effect of FKBP5 polymorphisms on peak response and response area under the curve (p = 0.0028 for rs3800374). In CRHR1, rs7209436, rs110402, and rs242924 were nominally associated with peak response (p rec = 0.0029-0.0047). We observed interactions between trait anxiety and rs7209436 and rs110402 in CRHR1 in association with baseline cortisol (p LRT = 0.0272 and p LRT = 0.0483, respectively)., Conclusions: We show association of variants in FKBP5 and CRHR1 with cortisol response to psychosocial stress. These variants were previously shown to be associated with neuropsychiatric disorders. These findings have implications for interindividual variation in HPA axis activity and potentially for the etiology of neuropsychiatric disorders.

Individual differences in subjective responses (SRs) to alcohol are moderated by genetic variants and may be risk factors for the development of alcohol use disorders. Variation in the GABA(A) α2 receptor subunit gene (GABRA2) has been associated with alcohol dependence (AD). Therefore, we examined whether individual differences in SRs, which reflect sensitivity to the effects of alcohol, are associated with variation in GABRA2. Sixty-nine healthy subjects (21-30 years) underwent a laboratory-based within-session cumulative oral alcohol dosing procedure, achieving a mean peak blood alcohol level of 100.4 mg/dl (standard error = 2.5). Subjective assessments were obtained throughout the session, including ascending and descending limbs of the alcohol curve. We genotyped single nucleotide polymorphisms (SNPs) across the chromosome 4 region spanning GABRA2 and analyzed the effect of genotype and haplotypes on subjective responses to alcohol. Population substructure was characterized through the use of ancestry informative markers. Individual SNP analysis demonstrated that carriers of the minor alleles for SNPs rs279858, rs279844, rs279845, rs279826, rs279828 and rs279836 had lower 'Negative' alcohol effects scores than individuals homozygous for the common allele at each SNP (P = 0.0060, P = 0.0035, P = 0.0045, P = 0.0043, P = 0.0037 and P = 0.0061, respectively). Haplotype effects of block 1 showed concordant results with SNPs in this block (P = 0.0492 and P = 0.0150 for haplotypes 1 and 4, respectively). The minor alleles for several of these SNPs have previously been associated with AD. Our findings provide further evidence that variation within GABRA2 is associated with attenuated negative responses to alcohol, a known risk factor for vulnerability to alcohol use disorders., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

The Asn40Asp variant (A118G) of the μ opioid receptor (OPRM1) gene is thought to contribute to the development and treatment of alcohol dependence. Employing positron emission tomography (PET), we first examined whether the single nucleotide polymorphism (SNP) modifies binding potential (BP(ND)) of the μ-selective ligand [(11)C]carfentanil in healthy control (Con) and 5-d abstinent alcohol-dependent (AD) subjects (unblocked basal scan). Second, we examined whether the allelic variants were associated with differences in OPRM1 occupancy by naltrexone (50 mg) in AD subjects. Con and AD carriers of the G allele (AG) had lower global BP(ND) at the basal scan than subjects homozygous for the A allele (AA). In AD subjects, naltrexone occupancy was slightly higher in AG subjects (98.9%) compared to AA subjects (93.1%), but this was not significant. We are the first to demonstrate using PET in healthy normal and AD subjects that the A118G SNP alters OPRM1 availability.

Hypothalamic-pituitary-adrenal (HPA) axis responses following naloxone administration have been assumed to provide a measure of opioid receptor activity. Employing positron emission tomography (PET) using the mu opioid receptor (MOR) selective ligand [(11)C] carfentanil (CFN), we demonstrated that cortisol responses to naloxone administration were negatively correlated with MOR availability. In this study, we examined whether naloxone-induced cortisol and adrenocorticotropin (ACTH) responses in 15 healthy control and 20 recently detoxified alcohol-dependent subjects correlated with delta opioid receptor (DOR) availability in 15 brain regions using the DOR-selective ligand [(11)C] methyl-naltrindole (MeNTL) and PET imaging. The day after the scan, cortisol responses to cumulative doses of naloxone were determined. Peak cortisol and ACTH levels and area under the cortisol and ACTH curve did not differ by group. There were negative relationships between cortisol area under curve to naloxone and [(11)C] MeNTL-binding potential (BP(ND)) in the ventral striatum, anterior cingulate, fusiform cortices, temporal cortex, putamen and a trend in the hypothalamus of healthy control subjects. However, in alcohol-dependent subjects, cortisol responses did not correlate with [(11)C]MeNTL BP(ND) in any brain region. Plasma ACTH levels did not correlate with [(11)C]MeNTL BP(ND) in either group. The study demonstrates that naloxone provides information about individual differences in DOR availability in several mesolimbic structures. The data also show that the HPA axis is intimately connected with mesolimbic stress pathways through opioidergic neurotransmission in healthy subjects but this relationship is disrupted during early abstinence in alcohol-dependent subjects., (© 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.)

Context: Unlike pituitary macroadenomas, microadenomas (micros) are not commonly associated with hypopituitarism. In clinical practice, we have observed that patients with ACTH-secreting micros have a higher than expected prevalence of central hypothyroidism (HT), and we speculated that this effect might be because of glucocorticoid-induced suppression of the hypothalamic-pituitary-thyroid axis., Objective: To determine whether there is a difference in the prevalence of central HT among ACTH micros compared to other types of microadenoma, and if so, to investigate whether this is directly related to the degree of hypercortisolism., Design, Setting and Patients: Retrospective study of 149 newly diagnosed patients with pituitary micros: 34 ACTH-secreting, 72 prolactin-secreting (PRLomas) and 43 clinically nonfunctioning adenomas (NFAs)., Main Outcomes Measures: Prevalence of central HT, correlation between normalized free T4 or TSH vs normalized urinary free cortisol (UFC) or salivary cortisol., Results: The prevalence of central HT was significantly higher in the ACTH compared to the non-ACTH adenomas: 18% (ACTH), 1% (PRL) and 0% (NFAs). The mean normalized free T4 was lower in the ACTH micros compared to the non-ACTH micros (1·29 ± 0·06 vs 1·50 ± 0·23, P = 0·0001). There was no correlation between the degree of hypercortisolism, as reflected by 24-h urine free cortisol and salivary cortisol, and free T4 or TSH levels among the ACTH adenomas. Similarly, there were no differences in mean UFC or salivary cortisol between ACTH adenomas with and without central HT. Following transsphenoidal adenomectomy, central HT recovered in three of six patients with ACTH micros., Conclusions: These findings suggest that patients with ACTH-secreting microadenomas should always, at a minimum, undergo testing for central HT. However, given the potential for recovery of thyroid function following cure of Cushing disease, we recommend withholding thyroid hormone replacement until after pituitary surgery., (© 2012 Blackwell Publishing Ltd.)

ACTH-secreting pituitary adenomas (Cushing's disease, CD) are the most frequent cause of Cushing's syndrome. To test whether the size of ACTH-secreting adenomas correlates with the degree of biochemical and clinical features of hypercortisolism, we retrospectively reviewed all newly diagnosed CD patients seen at our institution by two neuro-endocrinologists over a 10-year time period. We documented the number of clinical manifestations and baseline hormonal measurements. There were 37 microadenomas (μAs) and 16 macroadenomas (MAs). We sought to characterize the relationship between tumor size (μA vs. MA) and number of signs and symptoms of hypercortisolism and biochemical assessment of hypercortisolemia. There were no significant differences in mean age, BMI, or prevalence of hypertension and type 2 diabetes between the μA and MA groups. However, the MAs had fewer clinical manifestations of hypercortisolism (29.4% vs. 36.1%, P = 0.02) compared to μAs. There was a higher prevalence of easy bruisability and proximal muscle weakness in the μAs, but otherwise the prevalence of signs and symptoms were similar between groups. The MAs had a lower random serum cortisol (18.2 ± 2.4 vs. 25.9 ± 1.8 mcg/dl, P = 0.018), lower cortisol:ACTH ratio (0.25 ± 0.03 vs. 0.42 ± 0.05, P < 0.048), and lower cortisol:tumor diameter ratio (14.1 ± 2.2 vs. 56.8 ± 7.2, P < 0.0001) than the μAs. We conclude that tumor size does not directly correlate with the extent of hormonal activity in ACTH-secreting adenomas. Biochemical activity and clinical manifestations may be mild even in larger tumors, and therefore a high index of suspicion may be necessary to recognize hypercortisolism in pituitary MAs.

The mu opioid receptor system is altered in alcohol dependent (AD) subjects. Cortisol responses to opioid receptor antagonists are assumed to impart information about opioid receptor activity. In the present study we examined naloxone-induced cortisol responses in 18 healthy control (HC) and 25 recently detoxified AD subjects and then correlated the cortisol response with mu opioid receptor availability across 15 brain regions using positron emission tomography (PET) and the mu opioid receptor selective ligand [(11)C] Carfentanil (CFN). On average the AD subjects required twice the dose of naloxone to induce a peak cortisol response compared to the HC subjects. Using the rising slope of the cortisol curve (placebo to peak) as a metric we then went on to examine the relationship between cortisol responses to naloxone and [(11)C]CFN BP(ND). There were significant negative relationships between cortisol and [(11)C]CFN binding potential (BP(ND)) in multiple brain regions of HC subjects. However, cortisol responses did not correlate with [(11)C]CFN BP(ND) across any brain region in AD subjects. In summary, naloxone imparts information about individual differences in mu opioid receptor availability throughout the mesolimbic system in healthy individuals. However pathways governing the relationship between naloxone-induced cortisol and mu opioid receptor availability are disrupted during early abstinence in AD subjects., (Copyright © 2012 Elsevier Inc. All rights reserved.)