Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects.

The brain mineralocorticoid receptor and stress resilience.

Stress exposure activates the HPA-axis and results in the release of corticosteroids which bind to two receptor types in the brain: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). While the role of the GR in stress reactivity has been extensively studied, the MR has received less attention. Nevertheless, pioneering in-depth studies over the past two decades have shown the importance of the brain MR in the processing of stressful information.

Oral contraceptives may alter the detection of emotions in facial expressions.

A possible effect of oral contraceptives on emotion recognition was observed in the context of a clinical trial with a corticosteroid. Users of oral contraceptives detected significantly fewer facial expressions of sadness, anger and disgust than non-users. This was true for trial participants overall as well as for those randomized to placebo.

A common mineralocorticoid receptor polymorphism (I180V) interacts with life events in relation to perfectionism in eating disorders: a pilot study.

The stress response is regulated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). When the balance between GR and MR signalling is disturbed, one's capacity to cope with a stressful event is diminished. In this pilot study, we tested the hypothesis that an interaction between common variants in the MR (rs5522) or GR gene (rs41423247) and stressful life events influences perfectionism levels in a group of patients with an eating disorder (ED; n = 113).

Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior.

We tested if common mineralocorticoid receptor (MR) gene variants contribute to the variability in neuroendocrine control and behavioral reactivity as observed in humans. For that purpose we screened for genetic variability and tested functionality of the identified human MR gene variants in vitro. Four haplotypes were tested for transactivational capacity in vitro and showed profound significant differences when stimulated with cortisol.

Human mineralocorticoid receptor (MR) gene haplotypes modulate MR expression and transactivation: implication for the stress response.

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in secretion of corticosteroids which facilitate behavioural adaptation. These effects exerted by corticosteroids are mediated by two brain corticosteroid receptor types, the mineralocorticoid receptor (MR), with a high affinity already occupied under basal conditions and the glucocorticoid receptor (GR), with a low affinity only activated during stress. Here, we studied MR gene haplotypes constituted by the two single nucleotide polymorphisms MR-2G/C (rs2070951) and MRI180V (rs5522).

Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities.

Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood.

Objective: We examined the relationship between two main str systems, the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, with the metabolic syndrome and its components.

Design: The design was baseline data (yr 2004-2007) of a prospective cohort: the Netherlands Study of Depression and Anxiety (NESDA).

Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone.

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and results in the secretion of corticosteroids, which facilitate behavioral adaptation and promote the termination of the stress response. These actions exerted by cortisol are mediated by two brain corticosteroid receptor types: the high affinity mineralocorticoid (MR) and the low affinity glucocorticoid receptor (GR). Dexamethasone is a potent GR agonist with affinity to MR.

Tryptophan depletion affects the autonomic stress response in generalized social anxiety disorder.

In generalized social anxiety disorder (gSAD), serotonergic dysfunctions are found, as well as abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges. These findings raise the question whether these phenomena are interrelated. Therefore we designed a study in which two groups with nine pair wise age and gender matched gSAD patients (total of 10 men and 8 women), who were successfully treated with a selective serotonin reuptake inhibitor (SSRI), underwent a tryptophan depletion challenge (TD) or a placebo condition.

Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder.

Objectives: In affective disorders, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is a frequently observed phenomenon. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR gene (NR3C1) may be at the base of the altered reaction of the HPA axis to stress and subsequently related to the development and course of affective disorders. The aim of our study is to evaluate associations between GR gene polymorphisms and bipolar disorder (BD).

Mental performance in old age dependent on cortisol and genetic variance in the mineralocorticoid and glucocorticoid receptors.

Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce.

A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness.

Context: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes.

Objective: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation.

Design: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated.

Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production.

We assessed corticosteroid sensitivity in multiple sclerosis (MS) patients compared to control subjects, using an in vitro assay of dexamethasone (Dex) inhibition of lipopolysaccharide (LPS) stimulated-blood interleukin-6 production. Significantly higher concentrations of dexamethasone were needed to obtain 50%-inhibition (ID(50)) of in vitro LPS stimulated interleukin (IL)-6 production (28.4 x 10(-7) M) in relapsing-remitting MS (RRMS) patients compared to chronic progressive MS (CPMS) patients (6.

Very low levels of the glucocorticoid receptor beta isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry.

The hippocampus is an important target for glucocorticoid hormones. Glucocorticoid receptor (GR) mediated feedback in this area is important for control of behavioural adaptation. An alternative splice variant, the GRbeta (GRbeta) isoform, does not bind ligand and has been proposed to inhibit classic GRalpha-mediated transactivation of target genes.

Anxious-retarded depression: relation with plasma vasopressin and cortisol.

Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is related to melancholic or endogenous depression; however, the strength of this relationship depends on the definition of the specific depression subcategory. A two-dimensionally defined subcategory, anxious-retarded depression, is related to melancholic depression. Since arginine vasopressin (AVP) activates the HPA axis, and both major depression and the melancholic subcategory are associated with elevated plasma AVP levels, we investigated whether the plasma AVP level is also elevated in anxious-retarded depression, melancholic depression and anxious-retarded melancholic depression, and whether plasma AVP and cortisol levels are correlated in these subcategories.

Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse.

The aim of the study is to test whether fluvoxamine affects the function of the hypothalamic pituitary adrenal (HPA) axis in female borderline (borderline personality disorder, BPD) patients with and without a history of sustained childhood abuse. Special attention is given to the presence of comorbid major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The HPA axis of 30 female BPD patients with (n = 17) and without (n = 13) a history of sustained childhood abuse was challenged with a combined dexamethasone and corticotropin releasing hormone test (DEX/CRH test) before and after 6 (n = 14) and 12 (n = 16) weeks of fluvoxamine treatment (150 mg/day).

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

Background: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse.

Estimation of plasma serotonin using isopycnic centrifugation.

The valid measurement of the concentration of serotonin (5-HT) in blood plasma is important when using the platelet as a model for the serotonergic neuron. The assay is hampered by the release of 5-HT by (residual) platelets during the preparation for assay. We developed an isopycnic method that separates cells gently and completely from plasma by centrifuging a diluted Percoll density-gradient to which whole blood was added.