Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels

The hypothalamus-pituitary-adrenal (HPA) axis is vital for an organisms' response to physiological and psychological stress. Cortisol, secreted upon activation of the HPA axis, impacts on physiological systems throughout the organism. Responses to cortisol are influenced and modified by a number of factors, including corticosteroid binding globulin (CBG) levels. A major part of circulating cortisol is bound to CBG and only the unbound fraction is thought to be biologically active. The aim of the present study was to examine the modulating effect of CBG levels on hormonal responses following psychosocial stress in women using oral contraceptives (n=115) and in medication-free men (n=93). In women, CBG levels were negatively associated with ACTH and salivary cortisol and positively with total cortisol levels following the TSST. In men, positive associations were observed between CBG and ACTH and total cortisol levels following the TSST. CBG is an important regulatory element of HPA axis response patterns; therefore, CBG levels have to be taken into account as a potential modifier of ACTH and cortisol responses to psychosocial and pharmacological stimulation. Investigations of the consequences of long-lasting OC intake on the neuroendocrine stress regulation in women might be warranted.     

HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender

Data from five independent studies were reanalyzed in order to investigate the impact of age and gender on HPA axis responses to an acute psychosocial laboratory stress task. The total sample consisted of 102 healthy subjects with 30 older adults (mean age: 67.3 y), 41 young adults (mean age: 23.5 y), and 31 children (mean age: 12.1 y). All participants were exposed to the Trier Social Stress Test (TSST).The stress protocol caused highly significant ACTH and total plasma cortisol responses in older and younger male and female adults (all p<0.0001) as well as salivary free cortisol responses in all six age and gender groups (all p<0.0001). Three-way ANOVAs for repeated measurement were applied to investigate the impact of age and gender on ACTH and cortisol responses. Results showed that the ACTH response to stress was higher in younger adults compared to older adults (main effect: p=0.009, interaction: p=0.06). Post hoc analyses revealed that there was no age effect in the subgroup of women (p=n.s.), while younger men had higher ACTH responses compared to older men (p=0.01). For total plasma cortisol, ANOVA results showed that the pattern of reactivity did not differ between age and gender groups (all interactional effects p=n.s.), although older females had hightened overall cortisol levels compared to the other groups, as proofed in post hoc analyses (all p<0.05). For free salivary cortisol, a significant main effect of gender (p=0.05) and an almost significant three-way-interaction (p=0.09) emerged. Post hoc analyses showed an elevated overall free salivary cortisol response in elderly men compared to elderly women (p=0.006), while no gender differences emerged in neither young adults nor children (both p=n.s.).In sum, the stressor induced significant HPA axis responses in all age and gender groups. The observed ACTH response patterns in young and elderly adults may suggest that a heightened hypothalamic drive in young men decreases with age, resulting in similar ACTH responses in elderly men and women. Alternative interpretations are also discussed. The data also supports the idea of a greater adrenal cortex sensitivity to ACTH signals in young females. Free salivary cortisol responses were elevated in elderly men compared to elderly women, an effect which cannot be explained by gender differences in perceived stress responses to the TSST. It can be speculated if corticosteroid binding globulin (CBG) and/or sex steroids are important modulators of these effects.     

Gender differences in hypothalamic-pituitary-adrenal (HPA) axis reactivity

The present study was designed to determine whether there are gender differences in hormonal response patterns to HPA axis activation. To this end, two methods of activating the HPA axis were employed: a standardized psychological stress test and a pharmacological challenge. Healthy subjects (mean age 23.4 years, SD 7.0 years) completed a naloxone challenge and/or the modified Trier Social Stress Test (TSST). For the naloxone challenge, two baseline blood samples were obtained. Placebo was then administered (0 min), followed by increasing doses of intravenous naloxone (50, 100, 200 and 400 microg/kg) at 30-min intervals. Post-placebo blood samples were collected at 15-min intervals for 180 min. The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic exercises. Three baseline and five post-TSST blood samples were drawn. Eighty subjects (53 male, 27 female) underwent the TSST. Following the psychological stressor, adrenocorticotropin (ACTH) and cortisol responses were significantly greater in male subjects compared to female subjects (z=-2.34, p=0.019 and z=-2.12, p=0.034, respectively). Seventy-two subjects (52 male, 20 female) underwent HPA axis activation induced by naloxone. In contrast to the TSST, cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=4.11, p<0.001). Forty-one subjects (25 male, 16 female) completed both the TSST and naloxone challenge. In this subset, ACTH and cortisol responses to the TSST did not differ significantly by gender, although the effect size was moderate to large. Adrenocorticotropin and cortisol responses to the naloxone challenge were significantly greater in female subjects compared to male subjects (z=2.29, p=0.022 and z=4.34, p<0.001, respectively). In summary, male subjects had greater HPA axis responses to a psychological stressor than female subjects, and females had greater hormonal reactivity than males to pharmacological stimulation with naloxone. Such differences are of interest as potential contributors to gender differences in health risks.     

Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress.

BACKGROUND: Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. METHODS: We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). RESULTS: Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). CONCLUSIONS: We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.     

Whites have a more robust hypothalamic-pituitary-adrenal axis response to a psychological stressor than blacks

OBJECTIVE: Differences in the hypothalamic-pituitary-adrenal (HPA) axis response to stress may confer differences in susceptibility to a variety of diseases. We hypothesized that whites would differ from blacks in HPA axis response to a psychological stressor. DESIGN: Healthy subjects aged 18-30 were recruited from Baltimore, Maryland. At initial assessment, they completed psychometric tests measuring anxiety, mood, and personality. Subjects then participated in the Trier Social Stress Test (TSST), which consisted of 10 min of public speaking and mental arithmetic exercises. Subjective anxiety was measured immediately pre- and post-TSST. Race effects on cortisol, adrenocorticotrophin (ACTH), and prolactin responses to the TSST were analyzed by GEE longitudinal analysis methods. The analysis controlled for gender, baseline hormone levels, socioeconomic factors, anxiety, mood, and dimensions of personality. RESULTS: Ninety-eight subjects participated in the TSST. Whites had 36% greater relative mean cortisol response than blacks (95% CI: 10-67%, P=0.004). Whites had significantly higher mean ACTH compared to blacks at 25 min after the start of the TSST (35%, 95% CI: 16-58% greater, P<0.001). There was no difference in prolactin response. Of note, whites and blacks did not differ in subjective anxiety response to the TSST. CONCLUSIONS: In sum, we found that whites have a more robust HPA axis response to the TSST compared with blacks, even after controlling for several socioeconomic and psychological factors. In contrast, we observed no difference in prolactin response. There were no differences in subjective response to the TSST to explain the difference in HPA axis response. Further study is indicated to explain this finding and to test whether it can be extrapolated to other forms of stress.     

Acute HPA axis responses, heart rate, and mood changes to psychosocial stress (TSST) in humans at different times of day

There is evidence showing that HPA axis responses to pharmacological provocation depend on time of day with larger cortisol responses in the afternoon and evening compared to the morning hours. However, it is still unknown whether HPA axis responses to psychological stress are affected by time of day and whether they can be assessed with equal reliability in the morning and afternoon, respectively. The present reanalysis is based on five independent studies conducted in the same laboratory by and. All subjects were confronted with the Trier Social Stress Test (TSST) either in the morning or in the afternoon. The total sample consisted of 180 adults with 115 younger (49 females, 66 males) and 65 older adults (32 females, 33 males). All ANCOVA results controlled for possible age and gender effects. Stress-related free salivary cortisol, total plasma cortisol and ACTH net increases did not differ according to time of day (all p = n.s.). However, as expected pre-stress free salivary and total plasma cortisol levels differed significantly between the morning and afternoon group (both p < 0.005), leading to a significantly higher free cortisol area under the curve (AUC) in the morning (p = 0.02). Taken together, these observations suggest that the adrenal glands may be more sensitive to ACTH in the morning. Additionally, higher basal salivary cortisol levels were related to a lower stress-related net increase in salivary cortisol (p = 0.02), total plasma cortisol (p < 0.0001), and marginally ACTH (p = 0.09). Stress-related heart rate increases did not differ between groups (p = n.s.). The finding that the TSST-induced mood change was differentially affected by time of day requires further exploration. We conclude that comparable HPA axis and heart rate stress responses to psychosocial stress can be measured in the morning and afternoon.     

Blunted HPA axis responsiveness to stress in atopic patients is associated with the acuity and severeness of allergic inflammation

Previously we could demonstrate attenuated responsiveness of the hypothalamus–pituitary–adrenal (HPA) axis to stress in patients with chronic allergic inflammatory disease (i.e., atopic dermatitis, allergic asthma).The present study was designed to investigate HPA axis function in an acute manifestation of allergy. Patients with seasonal allergic rhinitis (SAR; n = 20) and non-atopic controls (n = 20) were exposed to a standardized laboratory stressor (‘Trier Social Stress Test’; TSST). Cortisol responses to the TSST and cortisol awakening responses (CAR) were measured in SAR subjects while suffering from acute symptoms of SAR (pollen season), and during a non-active state of their disease (pollen-free season). To assess the acuity and severity of SAR, eosinophil and basophil numbers and SAR symptomatology were determined. Non-allergic control subjects were examined at identical times during the year. To control for possible sequence effects, a cross-over design was used. SAR patients showed significantly increased symptom severity (t = 9.4; p < .001) as well as eosinophil (F(1, 31) = 9.8; p < .01) and basophil (F(1, 38) = 6.4; p < .05) numbers during the pollen season when compared to a pollen-free period. When exposed to the TSST, significantly attenuated cortisol responses were found in SAR subjects during acute manifestation of the disease (pollen season) when compared to the pollen-free season (F(16, 456) = 1.65; p < .05). In SAR patients, there was a significant negative correlation between symptom severity and the cortisol response to the stressor (r = .53; p < .05). No significant between-group or between-condition differences with respect to the CAR could be determined (all p > .05). These findings support previous data of attenuated HPA axis responsiveness to stress in atopic conditions and further, suggest that HPA axis hyporesponsiveness in atopy may be linked to the severity of the allergic inflammatory process.     

Temperament and response to the Trier Social Stress Test

OBJECTIVE: The personality characteristics behavioural inhibition and neuroticism have been associated with mood and anxiety disorders and, in some studies, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We recently reported that low levels of Novelty Seeking were associated with elevated plasma cortisol responses to the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test in healthy adults with no psychiatric disorder. The present study tested the association between temperament and HPA axis function in the same group of subjects using a standardized psychosocial neuroendocrine stress test. METHOD: Subjects completed diagnostic interviews, questionnaires, and the Trier Social Stress Test (TSST). RESULTS: Novelty Seeking was inversely associated with plasma cortisol concentrations at baseline and throughout the TSST, but was not related to adrenocorticotropic hormone (ACTH) levels. CONCLUSION: Results of this study extend our previous finding in the Dex/CRH test to a psychosocial stress test. Future investigations are needed to replicate these findings and further elucidate how temperament and personality are linked to HPA function.     

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.     

Impact of oral contraceptive use on glucocorticoid sensitivity of pro-inflammatory cytokine production after psychosocial stress

We previously reported that women using oral contraceptives (OC) show blunted free cortisol responses to psychosocial stress compared to medication-free women. Low cortisol responses to stress have been shown to be associated with increased susceptibilities to chronic inflammatory and autoimmune processes in animal models and certain human diseases.To address the question if the blunted free cortisol response of OC users may be compensated at the level of the target tissue, we measured hypothalamus-pituitary-adrenal (HPA) axis activation and glucocorticoid (GC) sensitivity of pro-inflammatory cytokine production after psychosocial stress in 14 women using OC and 11 women in the luteal phase of the menstrual cycle.All subjects were exposed to the psychosocial stress paradigm 'Trier Social Stress Test' (TSST). Free cortisol was measured repeatedly before and after stress. GC sensitivity was assessed by dexamethasone (DEX) inhibition of lipopolysaccharide (LPS) stimulated production of interleukin-6 (IL-6) in whole blood, immediately before, as well as 10 and 60 min after the stress test.As expected, the stress test induced significant increases in free cortisol in luteal phase women, while OC users showed blunted responses (F=3.31;p<0.05). GC sensitivity showed different response patterns; In luteal phase women a slight but not significant decrease was observed throughout the experiment. In contrast, women using OC showed a significant increase in GC sensitivity after stress (F=3.559;p<0.05).These results show, that an increase in GC sensitivity of pro-inflammatory cytokine production may at least in part compensate the low cortisol levels seen in OC users after stress. This could be one mechanism to protect women using OC medication from chronic inflammatory and autoimmune diseases.     

Endocrine stress responses in TH1-mediated chronic inflammatory skin disease (psoriasis vulgaris)--do they parallel stress-induced endocrine changes in TH2-mediated inflammatory dermatoses (atopic dermatitis)?

In previous research we reported attenuated responsiveness of the hypothalamus-pituitary-adrenal (HPA) axis and further, an increased reactivity of the sympathetic adrenomedullary (SAM) system to stress in patients suffering from atopic dermatitis (AD). AD is a chronic inflammatory skin disease mainly triggered by TH(2)-dependent inflammatory processes. The specific goal of the present study was to investigate whether altered HPA axis and SAM system responsiveness to stress can also be found in TH(1)-mediated inflammatory conditions. Patients with psoriasis (PSO; n=23), a TH(1)-mediated inflammatory (autoimmune) skin disease and healthy controls (n=25) were exposed to a standardized laboratory stressor (TSST) which mainly consists of a free speech and a mental arithmetic task in front of an audience. To investigate HPA axis and SAM system responsiveness, cortisol, ACTH, and catecholamines were determined before and after the stress test. In addition, cortisol levels after awakening and cortisol levels during the day (short diurnal profile) were determined. In order to test feedback sensitivity of the HPA axis, a dexamethasone (DEX) suppression test (0.5 mg) was performed. Analysis of cortisol and ACTH levels after the stress test yielded no significant differences between PSO subjects and controls indicating no altered HPA axis function in this patient group. Further, no between-group differences were found in cortisol levels after awakening or during the day (short diurnal profile). Additionally, no difference between PSO and healthy subjects in the feedback sensitivity of the system could be found (DEX test). However, PSO patients showed elevated epinephrine (F(3,102)=4.7; p<0.005) and norepinephrine (F(3,135)=2.7; p<0.05) levels in response to the stress test when compared to the controls. These findings suggest no altered HPA axis responsiveness, but increased reactivity of the SAM system in TH(1)-mediated chronic inflammatory skin disease.     

In healthy young and elderly adults, hypothalamic-pituitary-adrenocortical axis reactivity (HPA AR) varies with increasing pharmacological challenge and with age, but not with gender

Background

Hypothalamic-pituitary-adrenocortical axis reactivity (HPA AR) is the key indicator of the psychophysiological response to stress. The HPA AR may vary with age and gender. To investigate these factors concurrently, the aims of the present study were to observe HPA AR (plasma ACTH and plasma cortisol) in response to a pharmacological challenge (dexamethasone/corticotropin releasing hormone test: DEX/CRH-test) and as a function of age and gender.

Method

19 young (10 females and 9 males; mean age = 24.05 years) and 23 elderly (11 females and 12 males; mean age = 71.61 years) healthy volunteers took part in the study. To assess HPA AR, participants underwent the combined DEX/CRH test applied with the following DEX doses: 0.75, 1.5, and 3.0 mg, respectively.

Results

A dose-dependent response was observed in young adult participants, but not in elderly participants. With increasing DEX doses, ACTH and cortisol values decreased in young adult participants, while the decrease was blunted among elderly compared to young adult participants. No differences were observed for gender.

Conclusions

Results point to diminished HPA axis sensitivity as an effect of normal aging, irrespective of gender. Therefore, altered HPA regulation in old age should be taken into account for developing new therapeutic approaches acting on the HPA axis and its receptor mechanisms.     

Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam

Little is known about effects of commonly used anxiolytic drugs on psychologically evoked responses of two major stress systems, the hypothalamic–pituitary–adrenal (HPA) and the sympathetic–adrenal–medullary (SAM) axis. The purpose of the present study was to assess effects of the anxiolytic alprazolam on responses of the HPA and the SAM axes to a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST). Forty-six healthy, non-smoking, non-medicated males, aged between 18 and 45 years, were invited once to the laboratory and received a single oral dose of 1 mg alprazolam or placebo, respectively, 1 h prior to the TSST. The secretion of ACTH, cortisol, epinephrine, norepinephrine as well as changes in heart rate, blood pressure, and psychological states (anxiety, wakefulness, good mood, calmness) in response to the TSST were measured. Subjects pre-treated with alprazolam showed a strongly blunted response of ACTH as well as total and free cortisol to the TSST. Whereas alprazolam-treated subjects displayed significantly lower systolic blood pressure immediately before the TSST, neither the secretion of epinephrine, norepinephrine nor changes of heart rate in response to the stress test differed from placebo-treated subjects. Regarding psychological parameters, alprazolam clearly decreased subjective ratings on the questionnaire scale “wakefulness” and increased ratings on the scale “good mood”, whereas ratings on scales assessing “state anxiety” or “agitation” were not affected.

In healthy subjects, we observed a dissociation of the effects of alprazolam on the endocrine and the autonomic response to psychosocial stress. The psychological responses seemed to be masked by sedative properties of alprazolam.     

Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression.

BACKGROUND: Major depressive disorder (MDD) is often complicated by anxiety symptoms, and anxiety disorders occur in approximately 30% of mood cases. This study examined the influence of anxiety comorbidity on the hypothalamic-pituitary-adrenal (HPA) axis response to stress in patients with MDD. METHODS: Untreated subjects with pure MDD (n = 15), MDD with comorbid anxiety disorders (n = 18), and pure anxiety disorders (n = 15) were recruited by advertising. Age- and gender-matched control subjects were recruited for each subject with a psychiatric diagnosis (n = 48). All subjects underwent a social stressor, the Trier Social Stress Test (TSST), and blood was collected for adrenocorticotropic hormone (ACTH) and cortisol assay. RESULTS: When all depressed patients (n = 33) were compared with their matched control subjects (n = 33), they showed a significantly greater ACTH response to the stressor; however, this exaggerated ACTH response was exclusively due to the depressed group with comorbid anxiety disorders. A similar but nonsignificant effect was observed in the cortisol response. Subjects with pure mood or pure anxiety disorders showed normal ACTH and cortisol responses to the TSST. All patient groups showed similar levels of TSST-induced anxiety. CONCLUSIONS: Comorbid anxiety disorders might play a role in the increased activation of the HPA axis observed in patients with major depression.     

Randomized controlled evaluation of the effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects

Psychosocial stress is a potent activator of the hypothalamus-pituitary-adrenal (HPA) axis. While neuroendocrine stress responses are essential for the maintenance of homeostasis, evidence suggests that excessive activation of the HPA axis constitutes a risk for disease and psychopathology. The purpose of the present study was to assess the effect of cognitive-behavioral stress management training on endocrine stress responses and cognitive appraisal under acute psychosocial stress among healthy young subjects. Forty-eight healthy, non-smoking male students without acute or chronic medical or psychiatric disorder on self report were randomly assigned to receive group-based cognitive-behavioral stress management training either before or after a standardized psychosocial stress test (Trier Social Stress Test, TSST). Endocrine and psychological stress responses were assessed with salivary free cortisol response and cognitive appraisal processes to the TSST. In comparison with the control group, subjects in the treatment group showed an attenuated endocrine response (F (2.55/117.41) = 3.81; P = 0.02; effect size f(2) = 0.35) to the TSST. In addition, subjects in the SIT group had lower stress appraisal and higher control expectancies (F (2/45) = 6.56; P = 0.003, effect size f(2) = 0.29) compared to controls. Short group-based cognitive-behavioral stress management training reduces the neuroendocrine stress response to an acute stressor in healthy subjects. Therefore, stress management training may prove useful in preventing detrimental effects of stress-induced neuroendocrine activation     

Hippocampal activation during a cognitive task is associated with subsequent neuroendocrine and cognitive responses to psychological stress

Increased activation of the hypothalamus pituitary adrenal (HPA) axis, marked by increased secretion of cortisol, is a biological marker of psychological stress. It is well established that the hippocampus plays an important role in the regulation of HPA axis activity. The relationship between cortisol (stress‐related elevation or exogenous administration) and the hippocampal‐related cognitive function is often examined. However, few human studies to date have examined the effect of stress on hippocampal activity and the interactions between stress‐induced activation of the HPA axis and hippocampal function during different phases of cognitive function. On the basis of our previous work, we hypothesized that group differences in stress‐sensitivity relate to differences in hippocampal‐related stress‐integration. To test this hypothesis, we conducted a functional MRI study using tasks known to involve the hippocampal formation: novel‐picture encoding, psychological stress, and paired‐picture recognition. On the basis of their cortisol responses to stress, we divided subjects into stress‐responders (increase in cortisol, n = 9) and nonresponders (decrease in cortisol, n = 10). Responders showed higher hippocampal deactivation during the stress task and lower recognition scores due to a larger number of misses. Intriguingly, stress‐responders showed significant differences in hippocampal activation already prior to stress, with higher levels of hippocampal activity during the picture encoding. Although effects of both cortisol and hippocampal activation on recognition were present in responders, similar effects were absent in the nonresponder group. Our results indicate that hippocampus plays an important role in adaptive behavioral responses. We hypothesize that states of hippocampal activation prior to stress might reflect states of vigilance or anxiety, which might be important for determining interindividual differences in subsequent stress response and cognitive performance. © 2009 Wiley‐Liss, Inc.     

Dopamine-β-Hydroxylase Activity is Necessary for Hypothalamo-Pituitary-Adrenal (HPA) Responses to Ether, and Stress-Induced Facilitation of Subsequent HPA Responses to Acute Ether Emerges as HPA Responses are Inhibited by Increasing Corticosterone (B)

To determine a role of norepinephrine (NE) in stress-induced HPA function, young male rats were treated with diethyldithiocarbamide (DDC) which inhibits dopamine-β-hydroxylase, the enzyme that synthesizes NE from dopamine (DA). DDC injected 5 h prior to ether stress stimulated ACTH and corticosterone (B) during this time, and there was no further HPA response to ether. To control for elevated B feedback in DDC effects on HPA responses to ether, rats were adrenalectomized (Adx) and replaced with no (0% B), moderate (40% B) and high (80% B) levels of steroid 5 d prior to DDC or saline with ether stress 5 h later; Sham-Adx rats were included. In Adx rats increasing B inhibited thymus weight, median eminence CRF content, pituitary and plasma ACTH. In saline-treated rats, ether 5 h later caused increased CRF content and plasma ACTH in Sham-Adx and Adx, 0%B, increased ACTH in Adx, 40%B, and no response in Adx, 80% B. B treatment did not alter catecholamine content, and DDC treatment reduced NE content in the paraventricular nuclei by 50–60% in all groups. 5 h after DDC, pituitary ACTH was decreased in all rats with B and plasma ACTH was increased in sham-Adx and Adx, 40%B; thus DDC caused significant, prolonged stress which should facilitate subsequent HPA responses to acute stress. There was no HPA response to ether in Sham-Adx, Adx, 0% or 40% B groups, but there was a marked ACTH response to ether in the Adx, 80%B group treated with DDC. We conclude that: 1) the HPA response to ether stress is probably mediated by catecholamines; 2) DDC does not stimulate responses in the HPA axis in the absence of B; and, 3) facilitation of HPA responses to acute stress depends on increased steady-state B signals. Facilitated responses are probably not mediated by catecholamines. The consequence of facilitation is that under conditions of chronic stress and elevated B concentrations, as in depression or anorexia nervosa in man, or adjuvent-induced arthritis in rats, the HPA axis is continually responsive to new stimuli.     

Hypothalamic-pituitary adrenal response to cholecystokinin-B receptor agonism is resistant to cortisol feedback inhibition

Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism of activation and its physiological relevance remain uncertain. Preliminary data suggest that the ACTH response to pentagastrin may be differentiated from the response to exogenous corticotropin releasing hormone (CRH) by its relative resistance to cortisol feedback inhibition. To more directly test the relationship between cortisol levels and ACTH response to pentagastrin, this study examined responses to pentagastrin (a) during a peak (8 a.m.) and a nadir (4 p.m.) period of endogenous cortisol secretion and (b) when cortisol levels were artificially reduced to low levels by administration of metyrapone. ACTH responses to pentagastrin were identical in the morning and afternoon, despite substantial differences in basal cortisol levels. Suppression of cortisol with metyrapone had little impact on ACTH response to pentagastrin. These data support the hypothesis that CCK-B receptor mediated activation of the HPA axis is relatively resistant to cortisol feedback inhibition. This differentiates it from CRH-mediated activation and raises the possibility that CCK could contribute to acute activation of the HPA axis even in the face of elevated basal cortisol levels, such as those seen in chronic stress or some psychiatric disorders.     

OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques

The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: (1) maternal separation in infant subjects at 6 months of age, (2) acute ethanol administration in adolescent subjects at 4 years of age, and (3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 min, 10 min, and 60 min following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 min following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele, lending further support to the argument that the rhesus and human allelic variants are functionally similar. Our results also suggest that OPRM1 variation may influence coping style, as well as alcohol-induced and postpartum levels of HPA axis activity and, as such, may modify vulnerability to alcohol use disorders and postpartum depression.