Higher Levels of Basal Serial CSF Cortisol in Combat Veterans With Posttraumatic Stress Disorder
ABSTRACT Results of basal peripheral cortisol measures in posttraumatic stress disorder (PTSD) have been variable. The authors' goal was to measure CSF cortisol concentrations, which more accurately reflect brain glucocorticoid exposure, in subjects with or without PTSD.
CSF was withdrawn from a subarachnoid catheter and plasma from a venous catheter, both indwelling, over a 6-hour interval to determine hourly plasma ACTH and cortisol concentrations and hourly CSF cortisol levels in eight well-characterized combat veterans with PTSD and eight matched healthy volunteers.
Mean CSF cortisol concentrations were significantly higher in the subjects with PTSD (3.18 ng/ml, SD=0.33) than in the normal volunteers (2.33 ng/ml, SD=0.50), largely due to higher CSF cortisol concentration nadirs. No group differences were observed in either plasma ACTH or peripheral (plasma or urinary free) cortisol. CSF corticotropin-releasing hormone and CSF cortisol concentrations were positively and significantly correlated.
Despite normal peripheral cortisol indexes in the veterans with PTSD, their CNS exposure to cortisol was greater than that of normal comparison subjects.
- SourceAvailable from: Dean G Kilpatrick
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- "Thus, studying the relationship between regulatory genes of the HPA axis and PTSD may be useful. There are many genes that influence HPA axis reactivity (Amstadter, Koenen, et al., 2009; Amstadter, Nugent, & Koenen, 2009; Koenen, 2007); however, CRH genes are seemingly particularly consequential (Baker et al., 2005; Smoller et al., 2005; Tyrka et al., 2009; van Gaalen, Stenzel-Poore, Holsboer, & Steckler, 2002). Of candidate gene studies of PTSD to date, few have examined genes influencing the HPA axis (Bachmann et al., 2005; Binder et al., 2008), with one prior study examining a CRH gene (Amstadter et al., 2011). "
ABSTRACT: Posttraumatic stress disorder (PTSD) is a moderately heritable anxiety disorder that may develop after exposure to trauma. However, only few genetic variants that relate to PTSD have been studied. This study examined the relationship between 12 single nucleotide polymorphisms (SNPs) in the corticotropin-releasing hormone receptor 1 gene (CRHR1) and post-disaster PTSD symptoms and diagnosis in adults exposed to 2004 Florida hurricanes. CRHR1 regulates the hypothalamic-pituitary-adrenal (HPA) axis; dysregulation of the HPA axis is characteristic of stress phenotypes. Final analyses were conducted in the European-American (EA) subsample (n=564) due to population stratification. After correction for multiple testing, rs12938031 and rs4792887 remained associated with post-hurricane PTSD symptoms. Additionally, rs12938031 was associated with post-hurricane diagnosis of PTSD. This study is the first to examine CRHR1 in relation to PTSD in adults, and provides evidence for the importance of CRHR1 variation in the etiology of PTSD. Although results are preliminary and require replication, they justify follow-up efforts to characterize how this gene relates to PTSD.Journal of anxiety disorders 08/2013; 27(7):678-683. DOI:10.1016/j.janxdis.2013.08.003 · 2.68 Impact Factor
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- "F-S and F-R lines therefore provide a translational tool for identifying underlying determinants of fear memory strength as well as susceptibility and resistance to fearrelated psychopathology. Alterations in circadian corticosteroid rhythms are proposed endophenotypes of anxiety disorders, affective disorders, and PTSD (Baker et al., 2005; Wichers et al., 2008; Lok et al., 2012). In nonhuman primates, cortisol levels correlate with defensive freezing (Kalin et al., 1998), whereas in humans, higher basal cortisol levels are positively correlated with fear learning (Pineles et al., 2012), fear anticipation, amygdala activation (Grillon et al., 2006; Merz et al., 2012), and fear-potentiated startle (Grillon et al., 2006). "
ABSTRACT: Genetic variability in the strength and precision of fear memory is hypothesised to contribute to the etiology of anxiety disorders, including post-traumatic stress disorder. We generated fear-susceptible (F-S) or fear-resistant (F-R) phenotypes from an F8 advanced intercross line (AIL) of C57BL/6J and DBA/2J inbred mice by selective breeding. We identified specific traits underlying individual variability in Pavlovian conditioned fear learning and memory. Offspring of selected lines differed in the acquisition of conditioned fear. Furthermore, F-S mice showed greater cued fear memory and generalised fear in response to a novel context than F-R mice. F-S mice showed greater basal corticosterone levels and hypothalamic corticotrophin-releasing hormone (CRH) mRNA levels than F-R mice, consistent with higher hypothalamic-pituitary-adrenal (HPA) axis drive. Hypothalamic mineralocorticoid receptor and CRH receptor 1 mRNA levels were decreased in F-S mice as compared with F-R mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was used to investigate basal levels of brain activity. MEMRI identified a pattern of increased brain activity in F-S mice that was driven primarily by the hippocampus and amygdala, indicating excessive limbic circuit activity in F-S mice as compared with F-R mice. Thus, selection pressure applied to the AIL population leads to the accumulation of heritable trait-relevant characteristics within each line, whereas non-behaviorally relevant traits remain distributed. Selected lines therefore minimise false-positive associations between behavioral phenotypes and physiology. We demonstrate that intrinsic differences in HPA axis function and limbic excitability contribute to phenotypic differences in the acquisition and consolidation of associative fear memory. Identification of system-wide traits predisposing to variability in fear memory may help in the direction of more targeted and efficacious treatments for fear-related pathology.European Journal of Neuroscience 08/2013; 38(9). DOI:10.1111/ejn.12337 · 3.67 Impact Factor
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- "The finding of a blunted corticosterone response to acute footshock exposure is of particular interest. Studies have shown that a substantial corticosterone response is necessary for homeostatic adaptation to stressors (McEwen and Gianaros, 2010; Rao et al, 2012), and a pathologically blunted cortisol response to stress in humans is believed to contribute to disorders such as post-traumatic stress disorder (Baker et al, 2005; LaBar and Cabeza, 2006; Luo et al, 2012). Therefore, a blunted initial corticosterone response and a failure to show changes with repeated exposure could contribute to the pathological responses to stress seen in the MAM model. "
ABSTRACT: Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examine behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing and corticosterone responses were quantified. We found that juvenile MAM-treated rats emit significantly more calls, spend more time vocalizing, emit calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline-treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals display a blunted HPA axis corticosterone response to acute footshock that does not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.Neuropsychopharmacology accepted article preview online, 8 May 2013; doi:10.1038/npp.2013.110.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2013; 40(3). DOI:10.1038/npp.2013.110 · 7.83 Impact Factor