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1.  Cognitive modulation of endocrine responses to CRH stimulation in healthy subjects 
Psychoneuroendocrinology  2009;35(3):451-459.
The hypothalamic-pituitary adrenal (HPA) axis is critical for biobehavioral adaptation to challenge and appears dysregulated in a range of psychiatric disorders. Its precise role in psychopathology remains unclear and discrepant and difficult to explain findings abound in the clinical literature. Basic research suggests this system is sensitive to psychosocial cues, but psychosocial milieu factors are rarely controlled or examined in psychiatric studies using biological probes of the HPA axis. To test the hypothesis that psychological factors might complicate HPA study results even in direct, pharmacological challenge paradigms, endocrine responses to corticotropin-releasing hormone (CRH) were examined under two different cognitive preparation conditions.
Healthy subjects (n=32) received standard instructions or a cognitive intervention (CI) prior to injection with CRH and placebo, given on separate days in random order. The CI combined access to control over drug exposure with novelty reduction and coping enhancement. Blood samples were obtained via intravenous catheter before and after CRH.
Cognitive intervention reduced corticotropin (ACTH) levels, but only when CRH was given first (intervention by order interaction). It did not reduce cortisol response. The CI and visit (1st or 2nd) both impacted cortisol levels on placebo day.
Modifiable psychological factors may amplify or inhibit HPA axis activity in pharmacological activation paradigms, including CRH stimulation tests. The factors manipulated by the CI (novelty/familiarity, control and coping) may have particular salience to the HPA axis. Differential sensitivity to such factors could impact results in studies applying biological HPA probes to psychiatric populations.
PMCID: PMC2824051  PMID: 19758763
stress; cortisol; ACTH, corticotropin-releasing hormone; control; coping
2.  Brief cognitive intervention can modulate neuroendocrine stress responses to the Trier Social Stress Test: Buffering effects of a compassionate goal orientation 
Psychoneuroendocrinology  2014;44:60-70.
The hypothalamic–pituitary–adrenal (HPA) axis is a critical mediator linking stress to health. Understanding how to modulate its reactivity could potentially help reduce the detrimental health effects of HPA axis activation. Social evaluative threat is a potent activator of this system. Access to control and coping responses can reduce its reactivity to pharmacological activation. Compassionate or affiliative behaviors may also moderate stress reactivity. Impact of these moderators on social evaluative threat is unknown. Here, we tested the hypotheses that interventions to increase control, coping, or compassionate (versus competitive) goals could reduce HPA-axis response to social evaluative threat.
Healthy participants (n = 54) were exposed to social evaluative threat using the Trier Social Stress Test (TSST). They were randomly assigned to receive one of four different instructions prior to the stressor: Standard TSST instructions (SI), standard instructions with access to “control” (SI Control), or one of two cognitive interventions (CI) that (1) increased familiarity and helped participants prepare coping strategies (CI Coping), or (2) shifted goal orientation from self-promotion to helping others (CI Compassionate Goals). ACTH and Cortisol were obtained before and after stress exposure via intravenous catheter.
Control alone had no effect. CI Compassionate Goals significantly reduced ACTH and Cortisol responses to the TSST; CI Coping raised baseline levels. Compassionate Goals reduced hormonal responses without reducing subjective anxiety, stress or fear, while increasing expression of pro-social intentions and focus on helping others.
Brief intervention to shift focus from competitive self-promotion to a goal orientation of helping-others can reduce HPA-axis activation to a potent psychosocial stressor. This supports the potential for developing brief interventions as inoculation tools to reduce the impact of predictable stressors and lends support to growing evidence that compassion and altruistic goals can moderate the effects of stress.
PMCID: PMC4120861  PMID: 24767620
HPA; Cortisol; ACTH; Stress; Psychosocial stress; Trier Social Stress Test; Compassion; Control; Coping
3.  OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques 
Psychoneuroendocrinology  2011;36(9):1303-1311.
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 minutes, 10 minutes, and 60 minutes 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 minutes 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.
PMCID: PMC3131436  PMID: 21459516
Opioids; Hypothalamic-Pituitary-Adrenal (HPA) Axis; Cortisol; Stress; Nonhuman Primate; Separation; Alcohol; Postpartum Depression
4.  The Combined Propranolol/TSST Paradigm – A New Method for Psychoneuroendocrinology 
PLoS ONE  2013;8(2):e57567.
Upon perception of a stimulus as stressful, the human brain reacts with the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), to mobilize energy resources to better cope with the stressor. Since the perception of the stressor is the initial stimulus, a synchronicity between the subjective perception of stress and the physiological stress reactivity should be expected. However, according to a recent meta-analysis, these associations are weak and inconsistent. The goal of the current study was to investigate the interaction between the SNS, HPA and subjective stress perceptions, by introducing an experimental manipulation of this interaction. For this purpose, we combined the SNS inhibitor propranolol with the Trier Social Stress Test, and measured endocrinological and psychological responses to the stressor. Thirty healthy male participants were recruited and randomly assigned to either a propranolol (PROP; n = 15) or placebo (PLC; n = 15) group. All subjects were administered 80 mg of propranolol 60 minutes prior to exposure to psychosocial stress. Salivary cortisol and alpha amylase (sAA), heart rate, blood pressure and subjective stress responses were assessed throughout the study. We observed significantly reduced sAA levels and heart rate increases in the PROP group in response to stress, with no effects of the drug on systolic or diastolic blood pressure changes. In line with previous studies, a significant increase in cortisol was seen in response to the stress exposure. Importantly, the cortisol increase was significantly higher in the PROP group. A typical increase in subjective stress could be seen in both groups, with no significant group differences emerging. Complementing previous work, this study further demonstrates a significant interaction between the HPA and the SNS during acute stress. The HPA activity was found to be elevated in the presence of a suppressed SNS in reactivity to the TSST.
PMCID: PMC3579809  PMID: 23451243
5.  The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses 
Neuropsychopharmacology  2010;36(4):793-804.
The lateral septum (LS) has been shown to have a key role in emotional processes and stress responses. However, the exact role of the LS on stress modulation is not clear, as previous lesion studies mostly used electrolytic lesions, thereby destroying the whole septal area, including medial components and/or fibers of passage. The aim of the present study was therefore, to investigate the effects of selective excitotoxic ablation of the LS on neuroendocrine and behavioral stress responses in rats. Bilateral ibotenic acid lesions of the LS increased hypothalamo–pituitary–adrenocortical (HPA) axis responses to forced swim stress indicated by enhanced plasma ACTH and corticosterone responses and higher stress-induced c-Fos-like immunoreactivity in the paraventricular hypothalamic nucleus. Moreover, LS-lesioned animals showed a more passive coping style in the forced swim test indicated by increased floating and reduced struggling/swimming behavior compared with sham-lesioned controls. Interestingly, intraseptal corticosteroid receptor blockade modulated behavioral stress coping but failed to change HPA axis stress responses. Further experiments aimed at elucidating underlying neurochemical mechanisms revealed that intraseptal administration of the selective 5-HT1A receptor antagonist WAY-100635 increased and prolonged stress-induced ACTH and corticosterone levels mimicking lesion effects, while the agonist 8-OH-DPAT suppressed HPA axis activity facilitating the inhibitory role of the LS. In addition, 8-OH-DPAT-injected animals showed increased active and decreased passive coping strategies during forced swimming suggesting antidepressant efficacy. Taken together, our data suggest that the LS promotes active stress coping behavior and is involved in a HPA-inhibitory mechanism that is at least in part mediated by septal 5-HT1A receptors and does not involve a glucocorticoid mediated feedback mechanism.
PMCID: PMC3055728  PMID: 21160468
forced swimming; HPA axis; ACTH; corticosterone; glucocorticoids; serotonin; mood/anxiety/stress disorders; neurochemistry; neuroendocrinology; neuropharmacology; septum; HPA axis; stress; coping; glucocorticoids
6.  Stressor paradigms in developmental studies: What does and does not work to produce mean increases in salivary cortisol 
Psychoneuroendocrinology  2009;34(7):953-967.
The stress response system is comprised of an intricate interconnected network that includes the hypothalamic–pituitary–adrenocortical (HPA) axis. The HPA axis maintains the organism’s capacity to respond to acute and prolonged stressors and is a focus of research on the sequelae of stress. Human studies of the HPA system have been facilitated enormously by the development of salivary assays which measure cortisol, the steroid end-product of the HPA axis. The use of salivary cortisol is prevalent in child development stress research. However, in order to measure children’s acute cortisol reactivity to circumscribed stressors, researchers must put children in stressful situations which produce elevated levels of cortisol. Unfortunately, many studies on the cortisol stress response in children use paradigms that fail to produce mean elevations in cortisol. This paper reviews stressor paradigms used with infants, children, and adolescents to guide researchers in selecting effective stressor tasks. A number of different types of stressor paradigms were examined, including: public speaking, negative emotion, relationship disruption/threatening, novelty, handling, and mild pain paradigms. With development, marked changes are evident in the effectiveness of the same stressor paradigm to provoke elevations in cortisol. Several factors appear to be critical in determining whether a stressor paradigm is successful, including the availability of coping resources and the extent to which, in older children, the task threatens the social self. A consideration of these issues is needed to promote the implementation of more effective stressor paradigms in human developmental psychoendocrine research.
PMCID: PMC2692557  PMID: 19321267
Salivary cortisol; Stressor paradigms; Human development
7.  Effects of an exercise and hypocaloric healthy eating intervention on indices of psychological health status, hypothalamic-pituitary-adrenal axis regulation and immune function after early-stage breast cancer: a randomised controlled trial 
Many women experience emotional distress, depression and anxiety after a diagnosis of breast cancer. Psychological stress and depression have been associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation that may adversely affect immune system functioning and impact upon survival. This study investigated the effects of a lifestyle intervention on indices of psychological health status, HPA axis regulation and immune function in overweight women recovering from early-stage breast cancer treatment.
A total of 85 women treated for breast cancer 3 to 18 months previously were randomly allocated to a 6-month exercise and hypocaloric healthy eating program plus usual care or usual care alone (control group). Women in the intervention group received three supervised exercise sessions per week and individualized dietary advice, supplemented by weekly nutrition seminars. Depressive symptoms (Beck Depression Inventory version II: BDI-II), perceived stress (Perceived Stress Scale: PSS), salivary diurnal cortisol rhythms; inflammatory cytokines (IL-6 and Tumor necrosis factor-α), leukocyte phenotype counts, natural killer (NK) cell cytotoxicity and lymphocyte proliferation following mitogenic stimulation were assessed at baseline and 6-month follow up.
Compared with the control group, the intervention group exhibited a reduction in depressive symptoms (adjusted mean difference, 95% confidence intervals (95% CI): −3.12, −1.03 to −5.26; P = 0.004) at the 6-month follow-up but no significant decrease in PSS scores (−2.07, −4.96 to 0.82; P = 0.16). The lifestyle intervention also had a significant impact on diurnal salivary cortisol rhythm compared with usual care alone, as evidenced by an increase in morning salivary cortisol at the 6-month follow-up (P <0.04), indicating a change in HPA axis regulation. Women in the control group had higher total leukocyte, neutrophil and lymphocyte counts in comparison to the intervention group at the 6-month follow-up (P ≤0.05), whereas there was no difference in NK cell counts (P = 0.46), NK cell cytotoxicity (P = 0.85) or lymphocyte proliferation responses (P = 0.11) between the two groups.
Our results show that the lifestyle intervention resulted in a reduction in depressive symptoms and a normalisation of HPA axis regulation. Such changes could have important implications for long-term survival in women recovering from early-breast cancer treatment.
Trial registration
Current Controlled Trials: ISRCTN08045231
PMCID: PMC4052984  PMID: 24731917
8.  Effects of Chronic Plus Acute Prolonged Stress on measures of coping style, anxiety, and evoked HPA-axis reactivity 
Neuropharmacology  2012;63(6):1118-1126.
Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4°C, 6hrs/day, 14 days) followed on day 15 by a single 1-hr session of sequential acute stressors (social defeat, immobilization, swim). After CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further, CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD.
PMCID: PMC3427462  PMID: 22842072
PTSD; stress; coping style; anxiety; HPA-axis
9.  Noradrenaline and cortisol changes in response to low-grade cognitive stress differ in migraine and tension-type headache 
The Journal of Headache and Pain  2007;8(3):157-166.
The goal of this study was to explore the relationship between indicators of sympathoneural, sympathomedullar and hypothalamic-pituitary-adrenocortical (HPA) activity and stress-induced head and shoulder-neck pain in patients with migraine or tension-type headache (TTH). We measured noradrenaline, adrenaline and cortisol levels before and after low-grade cognitive stress in 21 migraineurs, 16 TTH patients and 34 controls. The stressor lasted for 60 min and was followed by 30 min of relaxation. Migraine patients had lower noradrenaline levels in blood platelets compared to controls. Pain responses correlated negatively with noradrenaline levels, and pain recovery correlated negatively with the cortisol change in migraineurs. TTH patients maintained cortisol secretion during the cognitive stress as opposed to the normal circadian decrease seen in controls and migraineurs. There may therefore be abnormal activation of the HPA axis in patients with TTH when coping with mental stress, but no association was found between pain and cortisol. A relationship between HPA activity and stress in TTH patients has to our knowledge not been reported before. In migraine, on the other hand, both sympathoneural activation and HPA activation seem to be linked to stress-induced muscle pain and recovery from pain respectively. The present study suggests that migraineurs and TTH patients cope differently with low-grade cognitive stress.
PMCID: PMC3476146  PMID: 17568991
Catecholamines; Cortisol; Migraine; Tension-type headache; Stress
10.  Antidepressants recruit new neurons to improve stress response regulation 
Molecular Psychiatry  2011;16(12):1177-1188.
Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.
PMCID: PMC3223314  PMID: 21537331
antidepressant; hippocampal neurogenesis; stress; depression; hypothalamo-pituitary-adrenal axis; immediate early gene
11.  The Combined Dexamethasone/TSST Paradigm – A New Method for Psychoneuroendocrinology 
PLoS ONE  2012;7(6):e38994.
The two main physiological systems involved in the regulation of the stress response are the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). However, the interaction of these systems on the stress response remains poorly understood. To better understand the cross-regulatory effects of the different systems involved in stress regulation, we developed a new stress paradigm that keeps the activity of the HPA constant when exposing subjects to psychosocial stress. Thirty healthy male participants were recruited and randomly assigned to either a dexamethasone (DEX; n = 15) or placebo (PLC; n = 15) group. All subjects were instructed to take the Dexamethasone (2 mg) or Placebo pill the night before coming to the laboratory to undergo the Trier Social Stress Task (TSST). Salivary cortisol, salivary alpha amylase (sAA), heart rate, blood pressure and subjective stress were assessed throughout the protocol. As expected, the DEX group presented with suppressed cortisol levels. In comparison, their heart rate was elevated by approximately ten base points compared to the PLC group, with increases throughout the protocol and during the TSST. Neither sAA, nor systolic or diastolic blood pressures showed significant group differences. Subjective stress levels significantly increased from baseline, and were found to be higher before and after the TSST after DEX compared to placebo. These results demonstrate a significant interaction between the HPA and the SNS during acute stress. The SNS activity was found to be elevated in the presence of a suppressed HPA axis, with some further effects on subjective levels of stress. The method to suppress the HPA prior to inducing stress was found to completely reliable, without any adverse side effects. Therefore, we propose this paradigm as a new method to investigate the interaction of the two major stress systems in the regulation of the stress response.
PMCID: PMC3372469  PMID: 22701740
12.  Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability 
The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases.
We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS).
Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.
PMCID: PMC1804264  PMID: 17300722
13.  Bouncing back - trauma and the HPA-axis in healthy adults 
European Journal of Psychotraumatology  2010;1:10.3402/ejpt.v1i0.5844.
Dysregulation of the hypothalamic–pituitary–adrenal (HPA)-axis is thought to underlie stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed (TE) adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relations between trauma exposure, stress regulation, and psychopathology.
Mentally healthy TE subjects were compared with non-trauma-exposed (NE) healthy controls. To distinguish between the potential effects of childhood trauma and adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test.
The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning.
Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role.
PMCID: PMC3402002  PMID: 22893796
HPA-axis; cortisol; trauma; childhood trauma; adults; resilience
14.  Abnormal cortisol awakening response predicts worse cognitive function in patients with first-episode psychosis 
Psychological medicine  2010;41(3):463-476.
Cognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP).
In this study, 30 FEP patients and 26 controls completed assessment of the HPA axis (cortisol awakening response and cortisol levels during the day), perceived stress, recent life events, history of childhood trauma, and cognitive function. The neuropsychological battery comprised general cognitive function, verbal and non-verbal memory, executive function, perception, visuospatial abilities, processing speed, and general knowledge.
Patients performed significantly worse on all cognitive domains compared to controls. In patients only, a more blunted cortisol awakening response (that is, more abnormal) was associated with a more severe deficit in verbal memory and processing speed. In controls only, higher levels of perceived stress and more recent life events were associated with a worse performance in executive function and perception and visuospatial abilities.
These data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients.
PMCID: PMC3513413  PMID: 20529412
Cognition; cortisol; hypothalamic–pituitary–adrenal (HPA) axis; psychosis; schizophrenia; stress
15.  Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder 
BMC Psychiatry  2013;13:124.
Oxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non-pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI.
We sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493).
Results did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment.
These outcomes demonstrate that symptoms of MDD were reduced following effective treatment with an SSRI, and further, stress physiology was unlikely to be a key factor in this outcome. Further research is required to discriminate potential differences in underlying stress physiology for individuals with MDD who respond to antidepressant treatment, relative to those who experience treatment resistance.
PMCID: PMC3643878  PMID: 23627666
Major depressive disorder; Oxytocin; Cortisol; Hypothalamopuitary adrenal axis; SSRI
16.  CRH-stimulated cortisol release and food intake in healthy, non-obese adults 
Psychoneuroendocrinology  2009;35(4):607-612.
There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans.
We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm.
CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption.
These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity.
PMCID: PMC2843773  PMID: 19828258
stress; cortisol; CRH; appetite; HPA
17.  Multidrug-resistance gene 1-type p-glycoprotein (MDR1 p-gp) inhibition by tariquidar impacts on neuroendocrine and behavioral processing of stress 
Psychoneuroendocrinology  2007;32(0):1028-1040.
The multidrug-resistance gene 1-type p-glycoprotein (MDR1 p-gp) is a major gate-keeper at the blood-brain barrier (BBB), protecting the central nervous system from accumulation of toxic xenobiotics and drugs. In addition, MDR1 p-gp has been found to control the intracerebral access of glucocorticoid hormones and thus to modulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) system. In view of the implication of glucocorticoids in the control of behavior, we examined how acute pharmacological inhibition of MDR1 p-gp at the BBB by tariquidar (XR9576; 12 mg/kg, PO) impacts on the neuroendocrine and behavioral processing of stress in C57BL/6JIcoHim inbred mice.
Inhibition of MDR1 p-gp at the BBB did not alter emotional behavior at baseline. However, mice that were sensitized by water-avoidance stress, a mild psychological stressor, displayed significantly reduced anxiety-related behavior in the elevated plus-maze test when treated with tariquidar. Tariquidar, however, had no effect on stress-coping performance assessed in the forced swim test. Investigating the impact of acute MDR1 p-gp inhibition on the glucocorticoid system, we observed a significant attenuation of the mild stress-induced increase of plasma corticosterone after tariquidar administration. In order to examine whether the anti-anxiety effect of tariquidar in sensitized animals is mediated by glucocorticoids, the animals were treated with corticosterone (1 mg/kg, SC immediately after exposure to water-avoidance stress. Corticosterone caused a significant anxiolytic-like effect in this stress-related anxiety protocol, whereas tariquidar could not further enhance corticosterone’s anti-anxiety effects.
The current data show for the first time that pharmacological inhibition of MDR1 p-gp at the murine BBB by tariquidar alters emotional behavior and HPA axis activity. By facilitating the entry of corticosterone into the brain, tariquidar enhances feedback inhibition of the HPA system and in this way improves anxiety-related stress processing. These findings highlight a novel approach to the treatment of stress-related affective disorders in humans.
PMCID: PMC4370831  PMID: 17881135
MDR1 p-glycoprotein; tariquidar; stress; glucocorticoids; anxiety
18.  β-endorphin modulates the effect of stress on novelty-suppressed feeding 
Although stress is implicated in the pathophysiology of mood and anxiety disorders, not all individuals who suffer stressful life events develop psychopathology. Differential susceptibility to stress may be influenced by genetically mediated differences in hypothalamic-pituitary-adrenal (HPA) axis activity and moderation of the stress response by the opioid peptide β-endorphin (β-E). The present study investigated genetic contributions to coping behavior by examining anxious behavior of transgenic mice with varying capacities to synthesize β-E [B6.129S2-Pomctm1Low/J; regulated by insertion of a premature stop codon into one or both copies of the proopiomelanocortin (POMC) gene], both under normal conditions and following 3 min of forced swim (FS). Ten minutes after this stress exposure or a control manipulation, acutely food-deprived female and male transgenic mice were subjected to a novelty-suppressed feeding (NSF) test, during which their interaction with an almond slice located in the center of an open field box was measured. There was an interaction between genotype and stress for latency to approach the almond and whether or not the almond was approached, such that mice with low or absent β-E displayed a stronger aversion to novelty-feeding after stress exposure than did mice with normal levels. These data provide evidence for a moderating effect of β-E on the behavioral response to stress. Genotypic differences in anxious behavior emerged when mice were stressed prior to behavioral assessment, suggesting that β-E plays a role in coping behavior. These findings indicate that genetic variability in sensitivity of the β-E system to stress may contribute, at least in part, to heritable differences in stress reactivity as well as vulnerability to stress-related psychopathology.
PMCID: PMC3596765  PMID: 23503677
opioids; transgenic; anxiety; depression; mice; hyponeophagia; novelty
19.  High Cardiorespiratory Fitness Is Negatively Associated with Daily Cortisol Output in Healthy Aging Men 
PLoS ONE  2015;10(11):e0141970.
Physical fitness has salutary psychological and physical effects in older adults by promoting neuroplasticity and adaptation to stress. In aging, however, the effects of fitness on the hypothalamic-pituitary-adrenal (HPA) axis are mixed. We investigated the association between cardiorespiratory fitness and HPA activity in healthy elderly men (n = 22, mean age 68 y; smokers, obese subjects, those taking drugs or reporting recent stressful events were excluded), by measuring in saliva: i) daily pattern of cortisol secretion (6 samples: 30’ post-awakening, and at 12.00, 15.00, 18.00, 21.00, 24.00 h); and ii) the cortisol response to a mental challenge. Cardiorespiratory fitness (VO2max) was estimated using the Rockport Walking Test and the participants were assigned to high-fit (HF, ≥60°, n = 10) and low-fit (LF, ≤35°, n = 12) groups according to age-specific percentiles of VO2max distribution in the general population. At all daytimes, basal cortisol levels were lower in the HF than the LF group, most notably in the evening and midnight samples, with a significant main effect of physical fitness for cortisol levels overall; the area-under-the-curve for total daily cortisol output was significantly smaller in the HF group. Among the subjects who responded to mental stress (baseline-to-peak increment >1.5 nmol/L; n = 13, 5 LF, 8 HF), the amplitude of cortisol response and the steepness of recovery decline displayed an increasing trend in the HF subjects, although between-group differences failed to reach the threshold for significance. In conclusion, cardiorespiratory fitness in healthy aging men is negatively correlated with daily cortisol output and contributes to buffering the HPA dysregulation that occurs with advancing age, thus possibly playing a beneficial role in contrasting age-related cognitive and physical decline.
PMCID: PMC4631391  PMID: 26529517
20.  Model-Based Therapeutic Correction of Hypothalamic-Pituitary-Adrenal Axis Dysfunction 
PLoS Computational Biology  2009;5(1):e1000273.
The hypothalamic-pituitary-adrenal (HPA) axis is a major system maintaining body homeostasis by regulating the neuroendocrine and sympathetic nervous systems as well modulating immune function. Recent work has shown that the complex dynamics of this system accommodate several stable steady states, one of which corresponds to the hypocortisol state observed in patients with chronic fatigue syndrome (CFS). At present these dynamics are not formally considered in the development of treatment strategies. Here we use model-based predictive control (MPC) methodology to estimate robust treatment courses for displacing the HPA axis from an abnormal hypocortisol steady state back to a healthy cortisol level. This approach was applied to a recent model of HPA axis dynamics incorporating glucocorticoid receptor kinetics. A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels. Suppression of biologically available cortisol may be achieved through the use of binding proteins such as CBG and certain metabolizing enzymes, thus offering possible avenues for deployment in a clinical setting. Treatment strategies can therefore be designed that maximally exploit system dynamics to provide a robust response to treatment and ensure a positive outcome over a wide range of conditions. Perhaps most importantly, a treatment course involving further reduction in cortisol, even transient, is quite counterintuitive and challenges the conventional strategy of supplementing cortisol levels, an approach based on steady-state reasoning.
Author Summary
The hypothalamic-pituitary-adrenal (HPA) axis is one of the body's major control systems helping to regulate functions ranging from digestion to immune response to metabolism. Dysregulation of the HPA axis is associated with a number of neuroimmune disorders including chronic fatigue syndrome (CFS), depression, Gulf War illness (GWI), and posttraumatic stress disorder (PTSD). Objective diagnosis and targeted treatments of these disorders have proven challenging because they present no obvious lesion. However, the body's various components do not work in isolation, and it is important to consider exactly how their interactions might be altered by disease. Using a relatively simple mathematical description of the HPA axis, we show how the complex dynamical behavior of this system will readily accommodate multiple stable resting states, some of which may correspond to chronic loss of function. We propose that a well-directed push given at the right moment may encourage the axis to reset under its own volition. We use model-based predictive control theory to compute such a push. The result is counterintuitive and challenges the conventional time-invariant approach to disease and therapy. Indeed we demonstrate that in some cases it might be possible to exploit the natural dynamics of these physiological systems to stimulate recovery.
PMCID: PMC2613527  PMID: 19165314
21.  Pain and sensory detection threshold response to acupuncture is modulated by coping strategy and acupuncture sensation 
Acupuncture has been shown to reduce pain, and acupuncture-induced sensation may be important for this analgesia. In addition, cognitive coping strategies can influence sensory perception. However, the role of coping strategy on acupuncture modulation of pain and sensory thresholds, and the association between acupuncture sensation and these modulatory effects, is currently unknown.
Electroacupuncture (EA) was applied at acupoints ST36 and GB39 of 61 healthy adults. Different coping conditions were experimentally designed to form an active coping strategy group (AC group), who thought they could control EA stimulation intensity, and a passive coping strategy group (PC group), who did not think they had such control. Importantly, neither group was actually able to control EA stimulus intensity. Quantitative sensory testing was performed before and after EA, and consisted of vibration (VDT), mechanical (MDT), warm (WDT), and cold (CDT) detection thresholds, and pressure (PPT), mechanical (MPT), heat (HPT) and cold (CPT) pain thresholds. Autonomic measures (e.g. skin conductance response, SCR) were also acquired to quantify physiological response to EA under different coping conditions. Subjects also reported the intensity of any acupuncture-induced sensations.
Coping strategy was induced with successful blinding in 58% of AC subjects. Compared to PC, AC showed greater SCR to EA. Under AC, EA reduced PPT and CPT. In the AC group, improved pain and sensory thresholds were correlated with acupuncture sensation (VDTchange vs. MI: r=0.58, CDTchange vs. tingling: r=0.53, CPTchange vs. tingling; r=0.55, CPTchange vs. dull; r=0.55). However, in the PC group, improved sensory thresholds were negatively correlated with acupuncture sensation (CDTchange vs. intensity sensitization: r=-0.52, WDTchange vs. fullness: r=-0.57).
Our novel approach was able to successfully induce AC and PC strategies to EA stimulation. The interaction between psychological coping strategy and acupuncture sensation intensity can differentially modulate pain and sensory detection threshold response to EA. In a clinical context, our findings suggest that instructions given to the patient can significantly affect therapeutic outcomes and the relationship between acupuncture intensity and clinical response. Specifically, acupuncture analgesia can be enhanced by matching physical stimulation intensity with psychological coping strategy to acupuncture contexts.
Trial registration
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6882-14-324) contains supplementary material, which is available to authorized users.
PMCID: PMC4167271  PMID: 25175308
Coping strategy; Acupuncture; Acupuncture sensation; Pain; Sensory threshold
22.  Effortful Control and Context Interact in Shaping Neuroendocrine Stress Responses during Childhood 
Hormones and behavior  2014;66(2):457-465.
Trait and contextual factors can shape individual and group differences in hypothalamic-pituitary-adrenal (HPA) response to stress; but the ways in which these factors may interact with each other to modulate stress activity has rarely been examined. Here, we investigated whether the association between a temperamental self-regulatory trait – Effortful Control (EC) – and HPA axis stress response is moderated by type of laboratory stress in sixty-five children (35 boys). EC was measured at age 3 and 6 using age-appropriate laboratory batteries as well as mother reports. HPA axis responses were measured at age 7 by randomly assigning children to one of two laboratory stress tasks (frustration vs. fear). Results indicated that EC interacted with stress context in predicting cortisol response. Specifically, lower EC was associated with greater cortisol response (steeper reactivity slopes) in the context of a frustration stressor but this was reversed in a fear context where lower EC was associated with flatter, more gradual activation. It is likely that different components of EC, such as emotion regulation and attention, differentially interact with the stress context. These types of effects and interactions need to be more thoroughly understood in order to meaningfully interpret cortisol reactivity data and better characterize the role of the HPA axis in human psychopathology.
PMCID: PMC4148048  PMID: 25019964
HPA; salivary cortisol; stress; effortful control; temperament; fear; frustration; children
Brain research  2007;1186:212-223.
The hypothalamic-pituitary-adrenal (HPA) axis habituates, or gradually decreases its activity, with repeated exposure to the same stressor. During habituation, the HPA axis likely requires input from cortical and limbic regions involved in processing of cognitive information that is important in coping to stress. Brain regions such as the medial prefrontal cortex (mPFC) are recognized as important in mediating these processes. The mPFC modulates stress-related behavior and some evidence suggests that the mPFC regulates acute and repeated stress-induced HPA responses. Interestingly, corticotropin releasing hormone(CRH)-1 receptors, which integrate neuroendocrine, behavioral and autonomic responses to stress, are localized in the mPFC but have not been specifically examined with respect to HPA regulation. We hypothesized that CRH receptor activity in the mPFC contributes to stress-induced regulation of HPA activity and anxiety-related behavior, and that CRH release in the mPFC may differentially regulate HPA responses in acutely- compared to repeatedly-stressed animals. In the present experiments, we found that blockade of CRH receptors in the mPFC with the non-selective receptor antagonist, D-Phe-CRH (50ng or 100ng) significantly inhibited HPA responses compared to vehicle regardless of whether animals were exposed to a single, acute 30min restraint or to the eighth 30min restraint. We also found that intra-mPFC injections of CRH (20ng) significantly increased anxiety-related behavior in the elevated plus maze in both acutely- and repeatedly-restrained groups compared to vehicle. Together, these results suggest an excitatory influence of CRH in the mPFC on stress-induced HPA activity and anxiety-related behavior regardless of prior stress experience.
PMCID: PMC2175080  PMID: 18001698
prefrontal cortex; corticotropin releasing hormone; restraint; anxiety; ACTH; corticosterone
24.  Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress 
Psychoneuroendocrinology  2014;0:151-163.
Early life stress can alter hypothalamic pituitary adrenal (HPA) axis function. Differences in cortisol levels have been found in preterm infants exposed to substantial procedural stress during neonatal intensive care, compared to infants born full-term, but only a few studies investigated whether altered programming of the HPA axis persists past toddler age. Further, there is a dearth of knowledge of what may contribute to these changes in cortisol. This prospective cohort study examined the cortisol profiles in response to the stress of cognitive assessment, as well as the diurnal rhythm of cortisol, in children (n=129) born at varying levels of prematurity (24–32 weeks gestation) and at full-term (38–41 weeks gestation), at age 7 years. Further, we investigated the relationships among cortisol levels and neonatal procedural pain-related stress (controlling for multiple medical confounders), concurrent maternal factors (parenting stress, depressive and anxiety symptoms) and children’s behavioral problems. For each aim we investigate acute cortisol response profiles to a cognitive challenge as well as diurnal cortisol patterns at home. We hypothesized that children born very preterm will differ in their pattern of cortisol secretion from children born full-term, possibly depended on concurrent child and maternal factors, and that exposure to neonatal pain-related stress would be associated with altered cortisol secretion in children born very preterm, possibly in a sex-dependent way. Saliva samples were collected from 7-year old children three times during a laboratory visit for assessment of cognitive and executive functions (pretest, mid-test, end - study day acute stress profile) and at four times over two consecutive non-school days at home (i.e. morning, mid-morning, afternoon and bedtime - diurnal rhythm profile). We found that cortisol profiles were similar in preterm and full-term children, albeit preterms had slightly higher cortisol at bedtime compared to full-term children. Importantly, in the preterm group, greater neonatal procedural pain-related stress (adjusted for morphine) was associated with lower cortisol levels on the study day (p=0.044) and lower diurnal cortisol at home (p=0.023), with effects found primarily in boys. In addition, child attention problems were negatively, and thought problems were positively, associated with the cortisol response during cognitive assessment on the study day in preterm children. Our findings suggest that neonatal pain/stress contributes to altered HPA axis function up to school-age in children born very preterm, and that sex may be an important factor.
PMCID: PMC4268136  PMID: 25313535
cortisol; preterm; stress; HPA axis; pain; internalizing behavior; child; sex; low birth weight; maternal interaction
25.  A Randomized Trial on Mineralocorticoid Receptor Blockade in Men: Effects on Stress Responses, Selective Attention, and Memory 
Neuropsychopharmacology  2011;36(13):2720-2728.
Corticosteroids, released in high amounts after stress, exert their effects via two different receptors in the brain: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). GRs have a role in normalizing stress-induced effects and promoting consolidation, while MRs are thought to be important in determining the threshold for activation of the hypothalamic–pituitary–adrenal (HPA) axis. We investigated the effects of MR blockade on HPA axis responses to stress and stress-induced changes in cognitive function. In a double-blind, placebo-controlled study, 64 healthy young men received 400 mg of the MR antagonist spironolactone or placebo. After 1.5 h, they were exposed to either a Trier Social Stress Test or a non-stressful control task. Responses to stress were evaluated by hormonal, subjective, and physiological measurements. Afterwards, selective attention, working memory, and long-term memory performance were assessed. Spironolactone increased basal salivary cortisol levels as well as cortisol levels in response to stress. Furthermore, spironolactone significantly impaired selective attention, but only in the control group. The stress group receiving spironolactone showed impaired working memory performance. By contrast, long-term memory was enhanced in this group. These data support a role of MRs in the regulation of the HPA axis under basal conditions as well as in response to stress. The increased availability of cortisol after spironolactone treatment implies enhanced GR activation, which, in combination with MR blockade, presumably resulted in a decreased MR/GR activation ratio. This condition influences both selective attention and performance in various memory tasks.
PMCID: PMC3230495  PMID: 21881569
mineralocorticoid receptor; spironolactone; psychosocial stress; cortisol; memory; selective attention; clinical pharmacology/clinical trials; cognition; learning & memory; psychiatry & behavioral sciences; mineralocorticoid receptor; spironolactone; psychosocial stress; cortisol; memory; selective attention

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