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. Moreover, a membrane-bound MR mediating the rapid effects of cortisol was recently discovered. This review summarizes how the MR may play a role in stress resilience. Both preclinical and clinical studies suggest that the MR is an important stress modulator and influences basal as well as stress-induced HPA-axis activity, stress appraisal, and fear-related memories. These MR effects are mediated by both genomic and non-genomic MRs and appear to be at least partially sex-dependent. Moreover, the majority of studies indicate that high MR functionality or expression may confer resilience to traumatic stress. This has direct clinical implications. First, increasing activity or expression of brain MRs may prevent or reverse symptoms of stress-related depression. Second, individuals with a relatively low MR functionality may possess an increased stress susceptibility for depression. Nevertheless, the number of clinical MR studies is currently limited. In conclusion, the recent emergence of the MR as a putative stress resilience factor is important and may open up new avenues for the prevention and treatment of psychiatric disorders.

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. Although it is uncertain whether this is an effect of oral contraceptives or a pre-existing difference, future studies on the effect of interventions should control for the effects of oral contraceptives on emotional and cognitive outcomes.

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. A TD procedure temporarily decreases serotonergic neurotransmission. In order to activate the stress system the TD/placebo challenge was combined with a public speaking task. We assessed ANS responses, as measured with the promising new marker salivary alpha-amylase (sAA), and HPA-axis responses, as measured with salivary cortisol. The most important result was that the TD group showed a significant larger sAA response to the public speaking task as compared to the placebo group, reflecting hyperresponsivity of the ANS in this group, whereas no differences were seen in cortisol responses. This suggests that in gSAD there is a vulnerability of the ANS more than the HPA-axis.

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. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p=0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p=0.057) and slower processing speed (p=0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p=0.003), as well as impairments in attention (p=0.034) and processing speed (p=0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p=0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.

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). Both 6- and 12-week fluvoxamine treatments were associated with a significant and robust reduction of the adrenocorticotrophic hormone (ACTH) and cortisol response to the DEX/CRH test. The magnitude of the reduction was dependent on the presence of sustained childhood abuse, but not on the presence of comorbid MDD or PTSD: patients with a history of sustained childhood abuse showed the strongest reduction in ACTH and cortisol. In conclusion, Fluvoxamine treatment reduces the hyperresponsiveness of the HPA axis in BPD patients with a history of sustained childhood abuse. This effect is likely to be obtained in the first 6 weeks of treatment.

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. In this study this method was compared with the usual differential centrifugation method. The isopycnic method on average resulted in nine times lower levels of plasma 5-HT. This difference was linearly related to the number of residual platelets in plasma after differential centrifuging. The proportion of intra-individual variation decreased three-fold. Therefore, the use of a Percoll density-gradient may lead to a more precise and more accurate estimate of the level of plasma 5-HT. Copyright 2000 John Wiley & Sons, Ltd.