The relevance of differential response to trauma in an animal model of posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder affects 20%-30% of those exposed. Clinical studies employ stringent inclusion-exclusion criteria, yet animal studies include the entire exposed population as the study population. We examined the effect of grouping prestressed rats according to magnitude of response on the statistical analysis of results. METHOD: Response magnitude to predator exposure was assessed and used to group the animals into "diagnostic" groups. Two extremes were studied (clearly "maladapted" and clearly "well adapted" rats) using arbitrarily selected cutoff behavioral criteria (CBC). The data for the middle group were discarded for reasons of clarity. Hypothalamic-pituitary-adrenal axis and heart-rate variability were analyzed for the entire exposed population and then according to the CBC. RESULTS: A single 10-min exposure to a predator caused fear-related behaviors in only 25.3% of exposed rats. Compared with control subjects and well-adapted exposed rats, maladapted rats exhibited significantly higher plasma corticosterone and corticotropin concentrations, increased sympathetic activity, diminished vagal tone, and increased sympathovagal balance. These differences surfaced only when data were analyzed according to CBC.Animals respond to stress heterogeneously, resembling humans. Overlooking this heterogeneity may obscure the results of data analysis. CONCLUSIONS: Animals can be divided into distinct groups according to magnitude of response and be studied accordingly.     

Anisomycin, a protein synthesis inhibitor, disrupts traumatic memory consolidation and attenuates posttraumatic stress response in rats.

BACKGROUND: Paradoxical changes in memory represent a troublesome characteristic of posttraumatic stress disorder (PTSD). Exceptionally vivid intrusive memories of some aspects of the trauma are mingled with patchy amnesia regarding other important aspects. Molecular studies of the memory process suggest that the conversion from labile short-term memory into long-term fixed traces involves protein synthesis. This study assessed the effects of administration of anisomycin, a protein synthesis inhibitor, after initial exposure, after exposure to a cue associated with triggering experience, and after reexposure to the triggering trauma in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in rats that were exposed to predator stress, with and without microinjection of anisomycin. RESULTS: Microinjection of anisomycin before and after stress exposure reduced anxiety-like and avoidant behavior, reduced the mean startle amplitude, and reversed the stress-induced habituation deficit 7 days later. The persistent anxiety-like behaviors that were seen after stress exposure do not appear to be sensitive to anisomycin after reexposure to a cue associated with the event or after reexposure to the index experience. CONCLUSIONS: Disruption of the process of traumatic memory consolidation may be useful for mitigating PTSD symptoms.     

Effects of metyrapone on hypothalamic-pituitary-adrenal axis and sleep in women with post-traumatic stress disorder.

BACKGROUND: Metyrapone blocks cortisol synthesis which results in removal of negative feedback, a stimulation of hypothalamic corticotropin releasing factor (CRF) and a reduction in delta sleep. We previously reported a diminished delta sleep and hypothalamic-pituitary-adrenal (HPA) response to metyrapone in men with post-traumatic stress disorder (PTSD). In this study, we aimed to extend these findings to women. METHODS: Three nights of polysomnography were obtained in 17 women with PTSD and 16 controls. On day 3, metyrapone was administered throughout the day up until bedtime. Plasma adrenocorticotropic hormone (ACTH), cortisol, and 11-deoxycortisol were obtained the morning following sleep recordings the day before and after metyrapone administration. RESULTS: There were no significant between-group differences in hormone concentration and delta sleep at baseline. Relative to controls, women with PTSD had decreased ACTH and delta sleep responses to metyrapone. Decline in delta sleep was associated with the magnitude of increase in ACTH across groups. CONCLUSIONS: Similar to our previous findings in men, the ACTH and sleep electroencephalogram response to metyrapone is attenuated in women with PTSD. These results are consistent with a model of downregulation of CRF receptors in an environment of chronically increased CRF activity or with enhanced negative feedback regulation in PTSD.     

HPA axis dysregulation in mice overexpressing corticotropin releasing hormone.

BACKGROUND: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Male transgenic CRH-OE(2122) mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress. RESULTS: CRH-OE(2122) mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE(2122) mice did not differ significantly. In reaction to stress, CRH-OE(2122) mice showed a normal corticosterone response. CONCLUSIONS: The HPA axis abnormalities observed in CRH-OE(2122) mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE(2122) mice may model the neuroendocrine changes observed in major depressive disorder.     

Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with dysregulation of the hypothalamus pituitary adrenal (HPA) axis. Alterations include various responses to HPA axis stimulation, different basal hormone levels, and changes in glucocorticoid receptor (GR) numbers on lymphocytes. The functional significance of these latter changes remains elusive. METHODS: Twelve Bosnian war refugees with PTSD and 13 control subjects were studied. On 2 consecutive days, they collected saliva samples after awakening and at 11, 15, and 20 hours. Glucocorticoid (GC) sensitivity was measured by dexamethasone (DEX) inhibition of lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production in whole blood. RESULTS: The PTSD patients showed no cortisol response after awakening and had lower daytime cortisol levels (F = 14.57, p <.001). Less DEX was required for cytokine suppression in PTSD patients (IL-6: t = -2.82, p =.01; TNF-alpha: t = 5.03, p <.001), reflecting higher GC sensitivity of pro-inflammatory cytokine production. The LPS-stimulated production of IL-6, but not TNF-alpha, was markedly increased in patients (IL-6: F = 10.01, p <.004; TNF-alpha: F =.89, p =.34). CONCLUSIONS: In refugees with PTSD, hypocortisolism is associated with increased GC sensitivity of immunologic tissues. Whether this pattern reflects an adaptive mechanism and whether this is sufficient to protect from detrimental effects of low cortisol remains to be investigated.     

Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder

Background

Posttraumatic stress disorder (PTSD) has been associated with lower concentrations of cortisol and enhanced suppression of cortisol by dexamethasone, although discrepancies exist among reports. The objective of the study was to determine the pattern of cortisol responses in patients seeking treatment for PTSD resulting from a variety of traumatic experiences and to test whether cortisol responses are significantly related to childhood trauma, severity of symptoms, or length of time since trauma.

Methods

Salivary cortisol was measured at 8 am, 4 pm, and 10 pm on 2 consecutive days before and after a 10 pm dose of .5 mg dexamethasone in 17 psychotropic medication and substance-free subjects with PTSD and 17 matched control subjects.

Results

Repeated-measures analysis of variance (ANOVA) of the baseline salivary cortisol concentrations demonstrated a significant effect for group with higher concentrations in the PTSD group but no significant differences in responses to dexamethasone. The presence of childhood abuse did not significantly affect salivary cortisol concentrations, and there was no correlation between predexamethasone cortisol and either the severity of PTSD symptoms or the time since the index trauma.

Conclusions

Neither low basal concentrations nor enhanced suppression of cortisol are consistent markers of a PTSD diagnosis.     

Associations between HPA axis functioning and level of anxiety in children and adolescents with an anxiety disorder

The hypothalamus-pituitary-adrenal (HPA) axis becomes active in response to stress. Hence, increased levels of anxiety in children and adolescents may be associated with changes in HPA-axis functioning. The aim of this study was to test if level of anxiety or specific anxiety disorders were associated with basal HPA axis activity in children and adolescents with an anxiety disorder. In 99 8- to 16-year-olds with an anxiety disorder, basal cortisol levels were assessed. It was tested if (1) cortisol levels correlated with the level of self-reported anxiety and (2) if cortisol levels were different for individuals with different anxiety disorders. In girls, low levels of anxiety were associated with a stronger rise in early morning cortisol concentrations. In both boys and girls, harm avoidance predicted low cortisol concentrations after awakening. Separation anxiety and physical anxiety symptoms predicted cortisol concentrations at noon. Differences between individuals with different anxiety disorders were not found. More research is needed regarding mechanisms that explain the associations that were found, and to investigate if treatment may influence HPA axis functioning in children and adolescents with an anxiety disorder.     

Children suffering from separation anxiety disorder (SAD) show increased HPA axis activity compared to healthy controls

Research questions

Separation anxiety disorder (SAD) is one of the most common mental disorders in childhood, and one of the earliest emerging. Little is known about the association between SAD and the hypothalamic-pituitary-adrenocortical (HPA) axis activity. Therefore, the present study aimed at investigating this association in children suffering from separation anxiety compared to healthy controls.

Methods

A total of 31 children with diagnosed SAD (mean age: 8.45; 17 females, 14 males) and 25 healthy controls (HC; mean age: 9.74; 12 females, 13 males) took part in the study. All participants underwent psycho-physiological testing for HPA axis challenge. Testing consisted of a separation and a social exposure paradigm. Saliva samples to assess HPA axis-related cortisol secretion were gathered in parallel.

Results

Compared to healthy controls, children with SAD showed greatly increased HPA axis activity, as reflected by an increased cortisol secretion throughout the entire period of investigation. The rise of cortisol was already observed in anticipation of, but not following the separation paradigm. No gender-related differences of cortisol secretion were observed.

Conclusions

Separation anxiety disorder (SAD) in children is reflected in greatly increased HPA axis activity. Compared to healthy controls, children with SAD showed increased cortisol values from the beginning of, and throughout, the entire investigation. This pattern of results suggests that both the anticipation of a separation and a persistent hyperactivity of the HPA axis system leads to an increased cortisol secretion.     

Blunted ACTH response to dexamethasone suppression-CRH stimulation in posttraumatic stress disorder

Previous studies have suggested that patients with posttraumatic stress disorder (PTSD) have an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) system and a blunted ACTH response to corticotropin releasing hormone (CRH). The effects of two dexamethasone dosages (0.75 and 1.5 mg) on the ACTH and cortisol concentrations after CRH stimulation (100 μg) were studied in eight patients with PTSD and matched healthy control subjects. Compared to healthy subjects, patients with PTSD have a blunted ACTH response to CRH. Cortisol concentrations were only significantly influenced by dexamethasone dosage. Our results give further evidence for a central role of the pituitary in reflecting changes of the negative feedback sensitivity of the HPA system in patients with PTSD.     

Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone.

BACKGROUND: Alterations of mineralocorticoid receptor (MR) mediated negative feedback inhibition of cortisol might contribute to abnormalities of hypothalamic-pituitary adrenal (HPA) activity in posttraumatic stress disorder (PTSD). METHODS: In a placebo-controlled study, we examined 11 subjects with PTSD and 11 healthy controls between 14:00 and 21:00. After pretreatment with 3 g metyrapone to inhibit basal endogenous cortisol secretion, subjects orally received in randomized order .5 mg of the MR agonist fludrocortisone or placebo. Adrenocorticotropic hormone (ACTH), cortisol, and 11-deoxycortisol were measured every 30 min until 21:00. RESULTS: Compared to placebo, fludrocortisone led to a significant decrease of ACTH and cortisol that was similar in both groups. Subjects with PTSD had higher raw cortisol and higher normed (baseline-related) ACTH and 11-deoxycortisol values after metyrapone independent of treatment with fludrocortisone or placebo. CONCLUSIONS: While HPA responses after metyrapone seem to be stronger in PTSD compared to controls, no alterations of mineralocorticoid receptor function in PTSD were found in this study.     

Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults

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.     

Intranasal insulin attenuates the hypothalamic-pituitary-adrenal axis response to psychosocial stress

Previous studies have shown that intranasally administered insulin exerts an inhibitory influence on the basal hypothalamic-pituitary-adrenal (HPA) axis activity. To date, however, it remains unclear as to whether intranasal insulin does furthermore affect HPA axis responsiveness in situations of stress. Here, we tested whether intranasally administered insulin attenuates the HPA axis response to psychosocial stress. Fifty minutes before being exposed to the Trier Social Stress Test (TSST), 26 healthy young male participants received a single intranasal dose of human insulin (40 I.U.) or placebo in a placebo controlled, double-blind between-subject design. Plasma cortisol, saliva cortisol, heart rate, and blood pressure were measured at resting baseline and in response to the TSST. Plasma cortisol (P<.001) and saliva cortisol (P<.001) increased in response to stress, as did heart rate (P<.001) and blood pressure (P<.001). Intranasal insulin did not influence plasma or saliva cortisol, heart rate, blood pressure, blood glucose, and plasma insulin levels at baseline. However, intranasal insulin diminished the saliva cortisol (two-way ANOVA; treatment by time interaction: P=.05) and plasma cortisol (two-way ANOVA; treatment by time interaction: P=.05) response to the TSST without affecting heart rate, and blood pressure stress reactivity. Our data show that a single intranasal insulin administration effectively lowers stress-induced HPA axis responsiveness. Intranasal insulin may offer a therapeutic potential to prevent hyperactivity of the HPA system.     

Increased basal activity of the HPA axis and renin-angiotensin system in congenital learned helpless rats exposed to stress early in development

Learned helpless behavior has been successfully bred in rats and designated as a genetic animal model of human depression and/or anxiety. Since congenital learned helpless animals have an impaired stress response in adulthood, we examined the effects of early stressors (at postnatal day 7, 14 or 21) on the hypothalamic–pituitary–adrenal axis and the renin-angiotensin system. The functioning of the hypothalamic–pituitary–adrenal axis was monitored through changes in corticosterone plasma levels in the adult animals after acute exposure to cold stress and maternal deprivation early in development. Renin-angiotensin system functioning was assessed by plasma renin activity. Unstressed congenital learned helpless rats had corticosterone levels that were similar to control animals (congenital non-learned helpless rats not stressed during development), but unstressed plasma renin activity levels of congenital learned helpless rats were lower than congenital non-learned helpless rats. There was a step-wise increase in corticosterone plasma levels in the congenital learned helpless rats with age of acute presentation of either cold stress or maternal deprivation stress (day 7, 49%; day 14, 84%; and day 21, 543% for cold stress). However, these baseline corticosterone levels were significantly lower in congenital learned helpless rats compared to congenital non-learned helpless controls. Similarly, in response to early exposure to cold stress and maternal deprivation, there was an increase in plasma renin activity levels of congenital learned helpless rats with age of presentation to either stressors. However, this increase in plasma renin activity levels was not evident in congenital non-learned helpless controls. Taken together, these results suggest that exposure to stress early in development has long-term effects on both the hypothalamic–pituitary–adrenal axis and the renin-angiotensin system, two neuroendocrine indicators of stress responsivity.     

Blunted pituitary-adrenocortical stress response in adult rats following neonatal dexamethasone treatment

Glucocorticoids have a prominent impact on the maturation of the stress-related neuroendocrine system and on the postnatal establishment of adaptive behaviour. The present study aimed at investigating the stress responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis in young and adult rats after neonatal treatment with the synthetic glucocorticoid agonist, dexamethasone. Newborn male Wistar rats were injected s.c. with 1 microg/g dexamethasone on postnatal days 1, 3 and 5. Circulating adrenocorticotropic hormone (ACTH) and corticosterone concentrations were measured in the resting state and following a 30-min cold stress at the age of 10 days, as well as after a 30-min restraint stress at the age of 14 weeks. Also in adults, pituitary and adrenocortical hormone responsiveness was evaluated after i.v. administration of 2 microg/kg corticotropin releasing hormone (CRH). In addition, glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities were assessed in the pituitaries of adult rats. The results showed that at day 10 basal ACTH concentration was elevated while the cold stress-evoked ACTH response was attenuated in the dexamethasone-treated rats. As adults, treated rats showed a suppressed elevation of both ACTH and corticosterone plasma concentrations in response to restraint, while basal hormonal concentrations were not altered. There was no difference in the magnitude of the CRH-induced elevation of ACTH and corticosterone concentrations initially; however, the dexamethasone-treated animals showed a prolonged secretion of both hormones. These animals also showed a selective decrease in pituitary GR binding capacity. Neonatal dexamethasone treatment strongly suppressed body weight gain, and adrenal and thymus weights in the early phase of postnatal development. By adulthood, the body and adrenal weights were normalized while thymus weight was greater than in controls. These findings indicate that neonatal dexamethasone treatment permanently alters HPA axis activity by reducing stress responses to cold and restraint probably through supra-pituitary actions, and by decreasing the effectiveness of feedback through a diminished GR binding in the pituitary.     

海马NMDA受体调节严重烫伤应激后HPA轴兴奋性的相关机制研究

目的探寻海马N-甲基-D-天冬氨酸(NMDA)受体调节严重创伤应激后HPA轴过度兴奋的可能机制。方法以30%总体表面积(TBSA)Ⅲ度烫伤应激作为严重创伤应激模型,先通过地塞米松抑制试验检测严重烫伤应激后糖皮质激素(GC)负反馈功能的变化,再利用RT-PCR技术检测烫伤应激后海马糖皮质激素受体(GR)mRNA水平(其水平与负反馈功能密切相关)的变化特点,并观察烫伤应激前腹腔注射NMDA受体拮抗剂MK-801对烫伤应激后2hGRmRNA水平的影响。结果30%TBSAⅢ度烫伤应激后地塞米松抑制试验阴性,GC负反馈功能下降;烫伤应激后0.5、2、8、24、48h海马GRmRNA水平皆明显降低,尤以伤后2h最明显;与烫伤应激组相比,MK-8013mg/kg组GRmRNA水平显著上升,MK-8016mg/kg组海马GRmRNA水平进一步上升,盐水组GRmRNA水平无明显变化。结论海马NMDA受体调节严重烫伤应激后HPA轴的亢进是通过下调海马GR从而影响了GC在海马水平的负反馈引起的。     

Event-based prospective memory among veterans: The role of posttraumatic stress disorder symptom severity in executing intentions

Objective: Posttraumatic stress disorder (PTSD) has been linked with neuropsychological deficits in several areas, including attention, learning and memory, and cognitive inhibition. Although memory dysfunction is among the most commonly documented deficits associated with PTSD, our existing knowledge pertains only to retrospective memory. The current study investigated the relationship between PTSD symptom severity and event-based prospective memory (PM). Method: Forty veterans completed a computerized event-based PM task, a self-report measure of PTSD, and measures of retrospective memory. Results: Hierarchical regression analysis results revealed that PTSD symptom severity accounted for 16% of the variance in PM performance, F(3, 36) = 3.47, p < .05, after controlling for age and retrospective memory. Additionally, each of the three PTSD symptom clusters was related, to varying degrees, with PM performance. Conclusions: Results suggest that elevated PTSD symptoms may be associated with more difficulties completing tasks requiring PM. Further examination of PM in PTSD is warranted, especially in regard to its impact on everyday functioning.     

Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial.

BACKGROUND: Based on an earlier pilot study, as well as a theoretical consideration of its mechanism of action, we undertook a placebo-controlled, double-blind trial of mirtazapine in posttraumatic stress disorder. METHODS: Twenty-nine patients were randomized to receive drug up to 45 mg/day or placebo double-blind on a 2:1 ratio for 8 weeks, with data being available for analysis in 26. Primary outcome measures comprised the Short Posttraumatic Stress Disorder Rating Interview (SPRINT) Global Improvement item and total score. Secondary measures comprised the Davidson Trauma Scale, Structured Interview for Posttraumatic Stress Disorder and Hospital Anxiety Depression Scale. Adverse events were also measured. RESULTS: On the Short Posttraumatic Stress Disorder Rating Interview Global Improvement measure, rates of response were 64.7% and 20.0% for mirtazapine and placebo. Treatment effects in favor of mirtazapine were noted on the Short Posttraumatic Stress Disorder Rating Interview global, Structured Interview for Posttraumatic Stress Disorder, and Hospital Anxiety Depression Scale anxiety subscale scores. The drug was well tolerated. CONCLUSIONS: Mirtazapine was more effective than placebo on some measures in posttraumatic stress disorder and general anxiety symptoms.