Association of Serum Aldosterone and Plasma Renin Activity With Ambulatory Blood Pressure in African Americans: The Jackson Heart Study.

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.

Methylomic and transcriptomic predictors of one-month exposure to cortisol in healthy individuals.

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 (punadjusted < 0.005) and nine DEGs (punadjusted < 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 R2 = 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 R2 = 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.

Changes in Hemodynamic Response Function Resulting From Chronic Alcohol Consumption.

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.

The Relationship of Varenicline Agonism of α4ß2 Nicotinic Acetylcholine Receptors and Nicotine-Induced Dopamine Release in Nicotine-Dependent Humans.

INTRODUCTION: Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4ß2 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 α4ß2-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 α4ß2-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 α4ß2-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 α4ß2-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 α4ß2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.

Detecting Deception in Our Research Participants: Are Your Participants Who You Think They Are?

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.

A paradigm for examining stress effects on alcohol-motivated behaviors in participants with alcohol use disorder.

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.

Independent and Interactive Effects of OPRM1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers.

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.

Anxiety, Anxiety Sensitivity, and Perceived Stress as Predictors of Recent Drinking, Alcohol Craving, and Social Stress Response in Heavy Drinkers.

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.

The Prevalence and Specificity of Depression Diagnosis in a Clinic-Based Population of Adults With Type 2 Diabetes Mellitus.

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.

Family history of alcoholism is related to increased D2 /D3 receptor binding potential: a marker of resilience or risk?

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 D2 /D3 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 (BPND ) and change in [11 C]raclopride (ΔBPND ). 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 BPND was generally higher in FHP compared with FHN subjects across striatal subdivisions. There were no differences in ΔBPND across regions. Negative subjective drug effects were more pronounced in FHP than in FHN subjects. While FHN subjects evidenced the expected positive relationship between ΔBPND 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.

Comments and controversies: Piecing together the neurobiology of decision-making.

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.

Job Strain and the Cortisol Diurnal Cycle in MESA: Accounting for Between- and Within-Day Variability.

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.

VENOUS SAMPLING FOR CUSHING DISEASE: COMPARISON OF INTERNAL JUGULAR VEIN AND INFERIOR PETROSAL SINUS SAMPLING.

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.

Risky decision-making and ventral striatal dopamine responses to amphetamine: a positron emission tomography [(11)C]raclopride study in healthy adults.

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.

Differences in extinction of cue-maintained conditioned responses associated with self-administration: alcohol versus a nonalcoholic reinforcer.

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.

Second attempt to withdraw cabergoline in prolactinomas: a pilot study.

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.

Association of smoking with µ-opioid receptor availability before and during naltrexone blockade in alcohol-dependent subjects.

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.

Prolonged HPA axis dysregulation in postpartum depression associated with adverse early life experiences: A cross-species translational study.

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.

Disrupted executive cerebro-cerebellar functional connectivity in alcohol use disorder.

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.

Influence of OPRM1 Asn40Asp variant (A118G) on [11C]carfentanil binding potential: preliminary findings in human subjects.

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.