Basal Hypothalamic-pituitary-adrenal Axis Activity Research Articles

Maternal High-Fat Diet Multigenerationally Programs HPA Function and Behaviors in Male Rat Offspring.

Maternal environmental factors have been demonstrated to exert significant influences on the health of offspring. The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine stress system that can be influenced by early life challenges. Our previous research has revealed that the consumption of a high-fat diet (HFD) by pregnant and lactating rats leads to the programming of HPA axis activity in male offspring of the first generation (referred to as F1HFD/C). The present study aimed to investigate whether the observed remodeling of the HPA axis could be inherited by second-generation male offspring (referred to as F2HFD/C), following maternal HFD exposure. The results showed that F2HFD/C rats exhibited enhanced basal HPA axis activity, similar to their F1HFD/C ancestors. Moreover, F2HFD/C rats displayed exacerbated corticosterone responses to restraint and lipopolysaccharide-induced stress, but not to insulin-induced hypoglycemia stress. Furthermore, maternal HFD exposure significantly aggravated depression-like behavior in the F2 generation subjected to chronic unpredictable mild stress. To investigate the role of central calcitonin gene-related peptide (CGRP) signaling in maternal diet-induced programming of the HPA axis across generations, we conducted central infusion of αCGRP8-37, a CGRP receptor antagonist, in F2HFD/C rats. The results demonstrated that αCGRP8-37 attenuated depression-like behaviors and reduced the hyperresponsiveness of the HPA axis to restraint stress in these rats. Therefore, central CGRP signaling may contribute to maternal diet-induced programming of HPA axis across generations. In conclusion, our study provides evidence that maternal HFD consumption can lead to multigenerational programming of the HPA axis and behaviors in adult male descendants.

Overexpression of angiotensin converting enzyme 2 reduces anxiety-like behavior in female mice.

Accumulating evidence has revealed an intricate role for the renin-angiotensin system (RAS) in the progression or alleviation of stress-related disorders. Along these lines, the ‘pro-stress’ actions of angiotensin-II (Ang-II) are largely thought to be mediated by the angiotensin type-1a receptor (AT1aR). On the other hand, a counter regulatory limb of the RAS that depends on the conversion of Ang-II to angiotensin-(1–7) by angiotensin-converting enzyme 2 (ACE2) has been postulated to exert stress-dampening actions. We have previously found that augmenting ACE2 activity is potently anxiolytic and blunts stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in male mice. Whether increasing ACE2 activity also relieves stress and anxiety in females has not yet been determined. Consequently, this series of experiments tests the hypothesis that augmenting ACE2 expression is anxiolytic and dampens the activity of the HPA axis in female mice. Using the Cre-LoxP system, we generated female mice that were homo-, heterozygous or wild-type for a mutated allele resulting in ubiquitous overexpression of ACE2. Next, we used qPCR to determine that levels of ACE2 mRNA isolated from central and peripheral tissues was dependent on genotype. That is, mice homo- and heterozygous for the ACE2 overexpression had significantly greater levels of ACE2 mRNA relative to littermate matched wild-type controls. Interestingly, anxiety-like behavior as determined by the elevated plus maze, light-dark box and novelty-induced hypophagia tests was also affected by genotype. Specifically, ACE2 overexpression significantly decreased anxiety-like behavior in paradigms dependent on approach-avoidance conflict and novelty; however, locomotor activity was similar amongst the genotypes. Final experiments measured plasma corticosterone to evaluate whether increasing ACE2 alters basal and/or stress-induced HPA axis activity. In contrast to what was previously found in males, increasing ACE2 expression had no effect on plasma corticosterone under basal conditions or subsequent to an acute restraint challenge. Collectively, these results suggest that increasing ACE2 expression potently elicits anxiolysis in female mice without altering HPA axis activity.

Prenatal ethanol exposure induced disorder of hypothalamic-pituitary-adrenal axis-associated neuroendocrine metabolic programming alteration and dysfunction of glucose and lipid metabolism in 40-week-old female offspring rats

This study was designed to demonstrate disorder of hypothalamic-pituitary-adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration and dysfunction of glucose and lipid metabolism induced by prenatal ethanol exposure (PEE) in postnatal week 40 (PW40) female offspring rats. Pregnant Wistar rats were administrated 4 g/kg·d ethanol intragastrically from gestational day 11 until term delivery. After weaning, the female offspring were fed with high-fat diet until PW24, and suffered to unpredictable chronic stress (UCS) during PW38-40. Animal serum was collected to examine the changes in hypothalamic-pituitary-adrenal (HPA) axis activity, glucose and lipid metabolic phenotypes before and after UCS. We found that pups in the PEE group manifested a low birthweight at PW1 and an early catch-up growth pattern. Furthermore, a low basal activity of HPA axis continued to PW38 in the PEE group. On the basal condition, serum low-density lipoprotein-cholesterol (LDL-C) level was significantly increased and high-density lipoprotein-cholesterol (HDL-C) level was significantly decreased in the PEE group, while serum triglyceride, total cholesterol (TCH), glucose and insulin levels were not significantly changed. Under unpredictable chronic stress, serum insulin in the PEE group was significantly decreased, while the levels of serum triglyceride, TCH, LDL-C, and the ratio of LDL-C/HDL-C were significantly higher than those in the control. These results suggest that PEE increases the dysfunction of glucose and lipid metabolism in PW40 female offspring, which is related to the disorder of HPA axis-associated neuroendocrine metabolic programming alteration.

Sex-Dependent Modulation of Acute Stress Reactivity After Early Life Stress in Mice: Relevance of Mineralocorticoid Receptor Expression.

Early life stress (ELS) is considered a major risk factor for developing psychopathology. Increasing evidence points towards sex-dependent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as a contributing mechanism. Additionally, clinical studies suggest that the mineralocorticoid receptor (MR) may further confer genetic vulnerability/resilience on a background of ELS. The link between ELS, sex and the HPA axis and how this interacts with MR genotype is understudied, yet important to understand vulnerability/resilience to stress. We used the early life-limited nesting and bedding model to test the effect of ELS on HPA properties in adult female and male mice carrying a forebrain-specific heterozygous knockout for MR. Basal HPA axis activity was measured by circadian peak and nadir corticosterone levels, in addition to body weight and weight of stress-sensitive tissues. HPA axis reactivity was assessed by mapping corticosterone levels after 10 min immobilization. Additionally, we measured the effects of ELS on steroid receptor [MR and glucocorticoid receptor (GR)] levels in the dorsal hippocampus and medial prefrontal cortex (mPFC) with western blot. Finally, behavioral reactivity towards a novel environment was measured as a proxy for anxiety-like behavior. Results show that HPA axis activity under rest conditions was not affected by ELS. HPA axis reactivity after immobilization was decreased by ELS in females and increased, at trend-level in males. This effect in females was further exacerbated by low expression of the MR. We also observed a sex*ELS interaction regarding MR and GR expression in the dorsal hippocampus, with a significant upregulation of MR in males only. The sex-dependent interaction with ELS was not reflected in the behavioral response to novel environment and time spent in a sheltered compartment. We did find increased locomotor activity in all groups after a history of ELS, which attenuated after 4 h in males but not females regardless of condition. Our findings support that ELS alters HPA axis functioning sex-dependently. Genetic predisposition to low MR function may render females more susceptible to the harmful effect of ELS whereas in males low MR function promotes resilience. We propose that this model may be a useful tool to investigate the underlying mechanisms of sex-dependent and genetic vulnerability/resilience to stress-related psychopathology.

DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic–pituitary–adrenal axis activity and to early life emotional abuse

Depression is associated with alterations in hypothalamic–pituitary–adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance.

O9.8. STRESS AND COGNITIVE FUNCTION AMONG INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS: FINDINGS FROM THE NAPLS COHORT

BackgroundAccumulated evidence from non-human animal studies suggests that the prominent deficits in memory and executive function that characterise individuals with psychosis may, at least in part, be due to the effects of stress on the brain regions that support these functions. However, studies of patients with established psychosis have yielded inconsistent findings with regards to the relationship between stress and cognition, and research in high-risk populations is notably lacking. Utilising data from the North American Prodrome Longitudinal Study 2 (NAPLS 2), we aimed to further elucidate the relationship between stress (daily stressors, life events, and childhood trauma) and cognitive function in clinical high-risk (CHR) individuals and healthy controls (HC). We additionally explored the role of potential mediators [hypothalamic-pituitary-adrenal (HPA) axis function] and moderators (group status, sex, family history of illness).MethodsThe sample comprised 885 participants (CHR=646; HC=239) who completed measures of stress and cognitive function at the NAPLS 2 baseline assessment. Stress measures included the Daily Stress Inventory and a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale, both of which provided continuous measures of stress exposure (number of events) and distress (subjective feelings of distress). Participants were also interviewed using the Childhood Trauma and Abuse Scale to determine any exposure to childhood trauma (abuse, neglect, and bullying occurring prior to age 16 years). Basal HPA axis activity was determined via salivary cortisol samples obtained at the baseline assessment and standardised scores from selected subtests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) were used to derive two cognitive domain scores (memory and executive function). To examine relationships between stress and cognitive domain scores, linear regression analyses were performed on standardised variables.ResultsDaily stressor exposure, daily stressor distress, and life event exposure exhibited negative quadratic (i.e., inverted U-shaped) associations with both memory and executive function (P < 0.01 for all). In contrast, the reverse pattern (i.e., a negative linear relationship and a positive quadratic relationship) was shown in the model for life event distress and memory domain scores (P < 0.01) whilst trauma history showed only a trend-level association with poorer memory performance (P = 0.084). These relationships, which did not differ across CHR and healthy control groups, were largely unchanged after adjusting for demographic factors and salivary cortisol. Exploratory analyses suggested that trauma exposure and a family history of psychosis may moderate the relationship between daily stressors/life events and cognitive function.DiscussionIn this large sample of predominately CHR individuals, we observed that the association between stress and cognition is complex and differs across stressor types. The negative quadratic associations that we observed for daily stressor exposure, daily stressor distress, and life event exposure imply that whist lower levels of stress may facilitate memory and executive function, there may be a negative impact on cognition when these stressors become more frequent and distressing. Interventions aiming to minimise stress exposure and promote effective coping strategies might feasibly improve cognition in CHR individuals.

Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans

Aging is associated with increases in hypothalamic-pituitary-adrenal (HPA) axis activity that can predispose to metabolic and cognitive impairments. We investigated in elderly and young subjects whether intranasal insulin administration to the human brain reduces early-sleep nadir concentrations of adrenocorticotropin and cortisol, that is, indicators of baseline HPA axis activity. In within-subject comparisons, intranasal insulin (160 IU) or placebo was administered to 14 elderly (mean age 70.0 years) and 30 young (23.6 years) healthy subjects before bedtime. Sleep was polysomnographically assessed and blood samples were repeatedly collected. Elderly compared with young participants displayed increased early-sleep cortisol concentrations (p < 0.04) and reductions in slow wave and REM sleep (p < 0.001). Insulin administration reduced cortisol levels between 2300 hours and 0020 hours in the elderly (p = 0.03) but not young participants (p = 0.56; p = 0.003 for interaction). Findings indicate that central nervous insulin acts as an inhibitory signal in basal HPA axis activity regulation and suggest that intranasal insulin may normalize sleep-associated stress axis activity in older age.

Evidence for central hypercortisolism and elevated blood pressure in adolescent offspring of mothers with pre-eclampsia.

Maternal total and free cortisol concentrations are reduced in pre-eclampsia (PE) and gestational hypertension (GH). However, the effect of this on the hypothalamic-pituitary-adrenal (HPA) axis function in the offspring is unknown. We examined the basal HPA axis activity in adolescent offspring of mothers with pre-pregnancy hypertension/GH/PE. A total of 1182 participants (mean age 17·1 years) recruited from the Western Australian Pregnancy Cohort (Raine) Study provided fasting morning blood samples for basal HPA axis and concomitant clinical assessments, including blood pressure. Plasma ACTH, total cortisol, corticosteroid-binding globulin (CBG) and free cortisol calculated by Coolens' equation were measured from the blood samples collected at home before 10:00 am. Total plasma cortisol (689 ± 153 nmol/l vs 583 ± 172 nmol/l, P = 0·024), ACTH (15·5 ± 13 pmol/l vs 10·8 ± 5·1 pmol/l, P = 0·040) and calculated free cortisol (52 ± 21 nmol/l vs 42 ± 22 nmol/l, P = 0·052) were higher in the PE offspring than in controls. The pre-pregnancy hypertension group had evidence of a lower ACTH/plasma free cortisol ratio (0·22 vs 0·33 P = 0·020) and lower CBG (713 nmol/l vs 821 nmol/l, P = 0·004) compared with controls. Systolic blood pressure was elevated in the GH/PE group compared with controls (120 mmHg vs 116 mmHg, P = 0·006). Hypothalamic-pituitary-adrenal axis activity is increased in the adolescent offspring of mothers with pre-eclampsia. This may be an adaptation resulting from the reduced maternal cortisol during foetal life. The resulting mild hypercortisolism may have implications for long-term health outcomes and warrants further investigation.

Involvement of Endogenous Brain-Derived Neurotrophic Factor in Hypothalamic-Pituitary-Adrenal Axis Activity.

Brain-derived neurotrophic factor (BDNF) appears to be highly involved in hypothalamic-pituitary-adrenal (HPA) axis regulation during adulthood, playing an important role in homeostasis maintenance. The present study aimed to determine the involvement of BDNF in HPA axis activity under basal and stress conditions via partial inhibition of this endogenous neurotrophin. Experiments were conducted in rats and mice with two complementary approaches: (i) BDNF knockdown with stereotaxic delivery of BDNF-specific small interfering RNA (siRNA) into the lateral ventricle of adult male rats and (ii) genetically induced knockdown (KD) of BDNF expression specifically in the central nervous system during the first ontogenesis in mice (KD mice). Delivery of siRNA in the rat brain decreased BDNF levels in the hippocampus (-31%) and hypothalamus (-35%) but not in the amygdala, frontal cortex and pituitary. In addition, siRNA induced no change of the basal HPA axis activity. BDNF siRNA rats exhibited decreased BDNF levels and concomitant altered adrenocortoctrophic hormone (ACTH) and corticosterone responses to restraint stress, suggesting the involvement of BDNF in the HPA axis adaptive response to stress. In KD mice, BDNF levels in the hippocampus and hypothalamus were decreased by 20% in heterozygous and by 60% in homozygous animals compared to wild-type littermates. Although, in heterozygous KD mice, no significant change was observed in the basal levels of plasma ACTH and corticosterone, both hormones were significantly increased in homozygous KD mice, demonstrating that robust cerebral BDNF inhibition (60%) is necessary to affect basal HPA axis activity. All of these results in both rats and mice demonstrate the involvement and importance of a robust endogenous pool of BDNF in basal HPA axis regulation and the pivotal function of de novo BDNF synthesis in the establishment of an adapted response to stress.

Clinical safety and hypothalamic-pituitary-adrenal axis effects of the arginine vasopressin type 1B receptor antagonist ABT-436.

Arginine vasopressin type 1B receptor (V1B) receptor antagonism is considered a potential therapeutic for diseases with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. The aim of the present study was to evaluate the safety and pharmacodynamics of ABT-436, a selective V1B antagonist, in healthy adults. Healthy adults received daily oral doses of ABT-436 in two clinical trials. In a dose escalation trial, nine subjects received each of 100, 500, or 800mg ABT-436, or placebo, in the morning for 7-14days. In a crossover trial on two 7-day regimens, 20 subjects received 200mg ABT-436 each morning or each evening. Pharmacokinetics, measures of basal HPA axis activity, and safety were assessed in both trials. Mild gastrointestinal intolerance was more common with ABT-436 treatment, compared to placebo, and showed dose dependence. Mean increases and decreases of systolic blood pressure (at different times), and mean pulse increases, were observed in subjects who received 800mg ABT-436. Mean decreases of plasma adrenocorticotrophic hormone (ACTH), serum cortisol, urine total glucocorticoids, and urine cortisol, compared to placebo, were observed following 7 daily doses of 500 and 800mg ABT-436. Statistically significant mean differences of plasma ACTH, serum cortisol, and urine total glucocorticoids were observed between morning and evening regimens of 200mg ABT-436. The largest observed differences were near the times of maximum post-dose ABT-436 plasma concentrations. ABT-436 regimens of 200-800mg once daily (QD) for 7days attenuated basal HPA axis activity. The results support further evaluation of ABT-436 for treatment of disorders in which HPA axis dysregulation may have an etiologic role.

The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic–pituitary–adrenal axis hyperactivity

Obesity and diabetes are closely associated with hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type prostaglandin D(2) synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.

The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

AimTo elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.MethodsPlasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine.ResultsDiazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity.ConclusionThe results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.

Altered Psychobiological Responsiveness in Women With Irritable Bowel Syndrome

Although stress has been considered an important pathophysiological factor in irritable bowel syndrome (IBS), there is incomplete understanding of its physiological mechanisms. The current study was designed to compare diurnal hypothalamic-pituitary-adrenal (HPA) axis activity in IBS patients and controls and their psychobiological response to a psychosocial stressor. Basal and stimulated HPA axis activity was assessed in 57 women with IBS and 20 matched controls. Psychiatric comorbidity was assessed using a standardized clinical interview. Salivary morning cortisol and diurnal profile were obtained, and the Trier Social Stress Test (TSST) was administered. Levels of cortisol and adrenocorticotropic hormone (ACTH) were measured before and within 1 hour after the stressor. Overall stress experience and stress related to the TSST were assessed using standardized questionnaires. All subjects showed intact circadian variation of cortisol. However, IBS patients with predominant diarrhea exhibited substantially heightened cortisol levels at awakening (p < .03) and a blunted cortisol awakening response. In response to the TSST, patients exhibited significantly blunted cortisol (p < .05) and slightly attenuated ACTH secretion compared with controls. During the recovery period, ACTH levels were significantly lower (p < .04) in patients than those in healthy subjects. Women with IBS perceived higher stress susceptibility than control subjects did (p < .01). The enhanced morning cortisol levels in one subgroup of IBS patients may indicate an association between basal HPA axis activity and predominant bowel habit. The downregulated HPA axis reactivity in IBS after the TSST suggests a downregulated sensitivity of the endocrine system. On the contrary, all subjective stress ratings were increased in the IBS group, which may indicate increased stress susceptibility.

Recovery from Disrupted Ultradian Glucocorticoid Rhythmicity Reveals a Dissociation Between Hormonal and Behavioural Stress Responsiveness

Ultradian release of glucocorticoids is thought to be essential for homeostasis and health. Furthermore, deviation from this pulsatile release pattern is considered to compromise resilience to stress-related disease, even after hormone levels have normalised. In the present study, we investigate how constant exposure to different concentrations of corticosterone affects diurnal and ultradian pulsatility. The rate of recovery in pulsatile hypothalamic-pituitary-adrenal (HPA) activity after withdrawal of exogenous corticosterone is also examined. Finally, the behavioural and neuroendocrine responsiveness to an audiogenic stressor is studied. Adrenally intact male rats were subcutaneously implanted with vehicle, 40% or 100% corticosterone pellets for 7 days. The continuous release of corticosterone from these implants abolished diurnal and ultradian corticosterone variation, as measured with high-frequency automated blood sampling. Pellet removal on post-surgery day 8 allowed rapid recovery of endogenous rhythms in animals previously exposed to daily average concentrations (40%) but not after exposure to high concentrations (100%) of corticosterone. Behavioural and neuroendocrine responsiveness to stress was distinctly different between the treatment groups. Audiogenic stimulation 1 day after pellet removal resulted in a similar corticosterone response in animals previously exposed to 40% corticosterone or vehicle. The 40% pellet group, however, showed less and shorter behavioural activity (i.e. locomotion, risk assessment) to noise stress compared to 100% corticosterone and vehicle-treated animals. In conclusion, unlike the animals impanted with 100% corticosterone, we find that basal HPA axis activity in the 40% group, which had mean daily levels of circulating corticosterone in the physiological range, rapidly reverts to the characteristic pulsatile pattern of corticosterone secretion. Upon reinstatement of the ultradian rhythm, and despite the fact that these animals did not differ from controls in their response to noise stress, they did show substantial changes in their behavioural response to stress.

The relationship between basal and acute HPA axis activity and aggressive behavior in adults

The hypothalamic–pituitary–adrenal (HPA) axis seems to play a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. However, most human research on the role of the HPA axis in aggression has been focusing on highly aggressive children and adolescent clinical samples. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 20 healthy male and female adults. We used the Taylor Aggression Paradigm to induce and measure aggression. We assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Salivary free cortisol measures for the cortisol awakening response were obtained on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. Half of the subjects were provoked with the Taylor Aggression Paradigm to behave aggressively; the other half was not provoked. Acute HPA axis activity was measured four times, once before and three times after the induction of aggression. Basal cortisol levels were significantly and negatively related to aggressive behavior in the provoked group and explained 67% of the behavioral variance. Cortisol levels following the induction of aggression were significantly higher in the provoked group when baseline levels were taken into account. The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones.

Exogenous cortisol enhances aggressive behavior in females, but not in males

The hypothalamic-pituitary-adrenal (HPA) axis plays a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 48 healthy male and female adults. We pharmacologically enhanced cortisol levels and used the Taylor Aggression Paradigm (TAP) to induce and measure aggression (divided into three blocks). Participants either received an oral dose of 20 mg hydrocortisone (cortisol group) or a placebo (placebo group). Half of each group received high or low levels of provocation with the TAP, respectively. Before, we assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Participants in the cortisol group reacted more aggressively in the third block of the TAP compared to the placebo group. Furthermore, gender interacted with treatment: only females, but not males showed enhanced aggressive behavior after cortisol administration. There was no significant difference in males between the placebo and cortisol group. Basal HPA axis activity was negatively related to aggressive behavior, but again only in females and most strongly within the placebo group. This study provides the first evidence for a causal involvement of acute HPA axis activation in aggressive behavior in humans.

Molecular regulation of the hypothalamic‐pituitary‐adrenal axis in adult male guinea pigs after prenatal stress at different stages of gestation

Studies in humans and animals have demonstrated that maternal stress during fetal development can lead to altered hypothalamic-pituitary-adrenal (HPA) axis function and behaviour postnatally. We have previously shown adult male guinea pigs that were born to mothers exposed to a stressor during the phase of rapid fetal brain growth (gestational days (GD) 50, 51 and 52; prenatal stress (PS)50) exhibit significantly increased basal plasma cortisol levels. In contrast, male guinea pig offspring whose mothers were exposed to stress later in gestation (GD60, 61 and 62; PS60) exhibited a significantly higher plasma cortisol response to activation of the HPA axis. In the present study, we hypothesized that the endocrine changes in HPA axis function observed in male guinea pig offspring would be reflected by altered molecular regulation of the HPA axis. Corticosteroid receptors in the hippocampus, hypothalamus and pituitary were measured, as well as corticotropin-releasing hormone (CRH), pro-opiomelanocortin (POMC) and adrenal enzymes in the paraventricular nucleus, pituitary and adrenal cortex, respectively, by in situ hybridization and Western blot. PS50 male offspring exhibited a significant reduction in glucocorticoid receptor (GR) mRNA (P <0.01) in the CA3 region of the hippocampus and significantly increased POMC mRNA (P <0.05) in the pituitary, consistent with the increase in basal HPA axis activity observed. In line with elevated activity of the HPA axis, both PS50 and PS60 male offspring exhibited significantly higher steroidogenic factor (SF)-1 (P <0.001) and melanocortin 2 receptor (MC2-R) mRNA (P <0.001) in the adrenal cortex. This study demonstrates that short periods of prenatal stress during critical windows of neuroendocrine development affect the expression of key regulators of HPA axis activity leading to the changes in endocrine function observed in prenatally stressed male offspring. Further, these changes are dependent on the timing of the maternal stressor, a pattern that is emerging in human studies.

Effect of the Glucocorticoid Receptor Antagonist Org 34850 on Basal and Stress‐Induced Corticosterone Secretion

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.

Involvement of the hypothalamic-pituitary-adrenal axis in the antidepressant-like effects of mild hypoxic preconditioning in rats

The preconditioning (PC) by using mild intermittent hypobaric hypoxia (PC) increases a resistance of the brain to severe hypoxia/ischemia and various stresses. Recently, potent antidepressant-like effects of PC have been described in animal models of depression. In the present study, the impact of PC on the activity and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA) impaired in depression has been studied in the model of shock-induced depression in rats. PC completely prevented depressive-like behavior (54% reduction in ambulance, 59% reduction in rearing in the open field, 654% increase of the anxiety level in the elevated plus maze), the HPA hyperactivity and the impairment of HPA feedback regulation that appeared in response to the inescapable footshock. Not affecting basal HPA activity, PC remarkably enhanced the HPA reactivity to stresses and substantially up-regulated the expression of glucocorticoid receptors in the ventral hippocampus following footshock that apparently contributes to the mechanisms responsible for the antidepressant-like action of PC.

Interaction Between Oestrogen and Oxytocin on Hypothalamic‐Pituitary‐Adrenal Axis Activity

In addition to its role in reproduction, oxytocin has central actions modulating behavioural and hypothalamic-pituitary-adrenal (HPA) axis responses during late pregnancy and lactation. The hypothesis that ovarian hormones modulate the effects of oxytocin on HPA axis activity was studied in 7-day ovariectomised rats receiving oestradiol with or without progesterone replacement and intracerebroventricular (i.c.v) minipump infusion of oxytocin (100 ng/h). In an initial experiment, i.c.v. oxytocin had no effect on basal or restraint-stimulated plasma adrenocorticotrophic hormone (ACTH) and corticosterone concentrations or hypothalamic corticotrophin-releasing factor (CRF) mRNA expression with low oestradiol replacement alone but it had a stimulatory effect in the presence of low oestradiol and progesterone. To investigate further whether oestradiol modulates central actions of oxytocin, rats received low dioestrous (low), pro-oestrous (medium) or pregnancy (high) oestradiol replacement levels, yielding plasma concentrations of < 5, 17.3 +/- 4.5 and 258 +/- 32 pg/ml, respectively, with or without i.c.v. oxytocin. Oestradiol caused dose-dependent increases in basal plasma ACTH and corticosterone concentrations but decreased the ACTH response to restraint stress. In parallel to the changes in basal plasma ACTH, high oestrogen increased basal CRF hnRNA, CRF mRNA in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the pituitary gland, while decreasing restraint stress-stimulated levels. Intracerebroventricular administration of oxytocin reduced basal and stress-stimulated plasma ACTH, hypothalamic CRF hnRNA (30 min), CRF mRNA and pituitary POMC mRNA (4 h) levels parallel to the increases induced by elevating plasma oestradiol. The present study demonstrates the converse effects of oestradiol on basal and restraint stress-stimulated basal HPA axis activity, and that the ability of central oxytocin to inhibit HPA axis activity depends on the levels of circulating oestradiol.