Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder

Department of Psychiatry, Yale University School of Medicine, New Haven, Conn., USA.
American Journal of Psychiatry (Impact Factor: 12.3). 06/1997; 154(5):624-9. DOI: 10.1176/ajp.154.5.624
Source: PubMed


Corticotropin-releasing factor (CRF) and somatostatin both play important roles in mediating responses to acute and chronic stress. The purpose of this study was to measure CSF concentrations of CRF and somatostatin in patients with chronic combat-related post-traumatic stress disorder (PTSD) and comparison subjects.
Lumbar punctures for collection of CSF were performed in Vietnam combat veterans with PTSD (N = 11) and comparison subjects (N = 17). CSF concentrations of CRF and somatostatin were compared between the two groups.
CSF concentrations of CRF were higher in the PTSD patients than in the comparison subjects (mean = 29.0 pg/ml, SD = 7.8, versus mean = 21.9 pg/ml, SD = 6.0). This group difference remained significant after covariance for age. CSF somatostatin concentrations in PTSD patients were higher than those of the comparison subjects (mean = 19.9 pg/ml, SD = 5.4, versus mean = 13.7 pg/ml, SD = 8.0). However, covarying for age reduced the level of significance.
Higher CSF CRF concentrations in patients with PTSD may reflect alterations in stress-related neurotransmitter systems. The higher CSF CRF concentrations may play a role in disturbances of arousal in patients with PTSD.

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    • "During a stressful event, CRF acts as a hormone to initiate the hypothalamic-pituitary-adrenal axis response to stress, as well as a neurotransmitter to centrally modulate brain circuits required for behavioral and cognitive responses to stress [5] [6]. Evidence for central CRF hypersecretion has been found in patients with depression and PTSD [7] [8], and this central elevation in CRF is thought to contribute to both the mood and cognitive disruptions that characterize these disorders [9] [10]. In rodent models, where the CRF system is easily manipulated, many mnemonic processes have been demonstrated to be regulated by 0166-4328/© 2015 Elsevier B.V. All rights reserved. "
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    ABSTRACT: Stressful life events and stress-related psychiatric disorders impair sustained attention, the ability to monitor rare and unpredictable stimulus events over prolonged periods of time. Despite the link between stress and attentional disruptions, the neurobiological basis for stress regulation of attention systems remains underexplored. Here we examined whether corticotropin releasing factor (CRF), which orchestrates stress responses and is hypersecreted in patients with stress-related psychiatric disorders, impairs sustained attention. To this end, male and female rats received central infusions of CRF prior to testing on an operant sustained attention task (SAT), where rats were trained to discriminate signaled from non-signaled events. CRF caused a dose-dependent decrease in SAT performance in both male and female rats. Females were more impaired than males following a moderate dose of CRF, particularly during the middle part of the session. This sex difference was moderated by ovarian hormones. Females in the estrous cycle stage characterized by lower ovarian hormones had a greater CRF-induced attentional impairment than males and females in other cycle stages. Collectively, these studies highlight CRF as a critical stress-related factor that can regulate attentional performance. As sustained attention subserves other cognitive processes, these studies suggest that mitigating high levels of CRF in patients with stress-related psychiatric disorders may ameliorate their cognitive deficits. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jan 2016 · Behavioural Brain Research
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    • "Significant evidence suggests that CRH plays a role in this process as the central coordinator of the stress response. For instance, CRH is elevated in the cerebrospinal fluid (CSF) of patients diagnosed with PTSD and individuals with significant childhood trauma history (Bremner et al, 1997; Carpenter et al, 2004; Lee et al, 2005). Moreover, CRH receptor type 1 (Crhr1) polymorphisms moderate associations of childhood trauma with depression and anxiety (Bradley et al, 2008; Cicchetti et al, 2011). "
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    ABSTRACT: Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH over-expression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 x tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2 and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. qRT-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress while males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.Neuropsychopharmacology accepted article preview online, 05 November 2015. doi:10.1038/npp.2015.338.
    Full-text · Article · Nov 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Furthermore, acting via CRH receptor 1 (CRHR1), it increases c-Fos and TH expression and neuronal discharge in LC, with subsequent NE release in cortical and subcortical structures (Melia and Duman 1991; Schulz and Lehnert 1996). CRH levels are elevated in CSF of PTSD patients (Bremner et al. 1997; Baker et al. 1999). In addition to elevated levels of NE and CRH, the CSF of PTSD patients have reduced neuropeptide Y (NPY) concentrations, which are correlated with the severity of the disorder (Geracioti et al. 2001; Sah et al. 2009, 2014). "
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    ABSTRACT: Dysregulation of the central noradrenergic system is core feature of PTSD. Here, we examined molecular changes in locus coeruleus (LC) triggered by single prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal NPY. Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated CRH in central nucleus of amygdala.Following testing for anxiety on EPM, there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressor, perhaps mediated by the upregulation of influence of amygdalar CRH input and downregulation of Y2R presynaptic inhibition in LC. Results also demonstrate therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments.This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2015 · Journal of Neurochemistry
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