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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.

Overview Although various forms of stress experienced during adulthood can be antecedents for the onset of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD), stressful events suffered during childhood [...]

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. [ABSTRACT FROM AUTHOR]

Background. Frailty is an important geriatric condition with increased vulnerability to stressors (e.g., infection and injury) and for developing functional dependence and mortality. Impairments in signaling pathways, including neuroendocrine alterations, are thought to be involved in the etiology of frailty, but have not been well characterized to date. We evaluated whether higher levels and blunted diurnal variation of salivary cortisol are cross-sectionally associated with frailty burden. Methods. Two hundred fourteen community-dwelling women, 80-90 years old, from the Women's Health and Aging Study participated in this study between 2004 and 2005. Seven saliva samples were collected for cortisol measurement over a 24-hour period. Main outcomes were awakening, evening, and overall mean cortisol; diurnal amplitude; and rate of decline of cortisol level during morning hours. All cortisol concentrations were log-transformed. Frailty burden was calculated, based on a previously validated tool, as the number (0-5) of the following criteria present: weakness, exhaustion, weight loss, slowness, and inactivity. Results. Significant positive associations were found between frailty burden and evening cortisol ([beta] = 0.11, p = .04), and between frailty burden and 24-hour mean cortisol ([beta] = 0.07, p = .03). Increasing frailty burden was significantly associated with smaller declines in cortisol during morning hours ([beta] = 0.04, p = .02). Frailty burden of [greater than or equal to] 2 was associated with a smaller diurnal amplitude [beta] = -0.34, p = .03). Awakening cortisol was not significantly associated with frailty burden ([beta] = 0.01, p = .8). All analyses included adjustments for several important confounders. Conclusions, Our findings provide the first epidemiological evidence that higher levels and blunted diurnal variation of cortisol may be involved in the vulnerability and clinical presentation observed in frail older women. Key Words: Frailty--Salivary cortisol--Diurnal rhythm--HPA axis--Evening cortisol.