Resetting the Stress System with a Mifepristone Challenge.

Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes.

In 1968, Bruce McEwen discovered that H-corticosterone administered to adrenalectomised rats is retained in neurons of hippocampus rather than those of hypothalamus. This discovery signalled the expansion of endocrinology into the science of higher brain regions. With this in mind, our contribution highlights the saga of the brain mineralocorticoid receptor (MR) in three episodes.

From vasotocin to stress and cognition.

Sex and stress hormones coordinate experience and behaviour with physiological regulations. In the brain the sex hormones act to promote the repertoire of affiliative and reproductive behaviours. Stress hormones target in particular brain circuits underlying emotional arousal and cognition.

Glucocorticoid signaling and stress-related limbic susceptibility pathway: about receptors, transcription machinery and microRNA.

Background: Stress is essential for health, but if coping with stress fails, the action of the stress hormones cortisol and corticosterone (CORT) becomes dysregulated, precipitating a condition favorable for increased susceptibility to psychopathology. We focus on the question how the action of CORT can change from protective to harmful.

Approach: CORT targets the limbic brain, where it affects cognitive processes and emotional arousal.

Neuropharmacology of glucocorticoids: focus on emotion, cognition and cocaine.

Hormone pharmacology has been quite interesting in The Netherlands the past century and this contribution is dedicated to the glucocorticoid hormones underlying adaptation to stress. The story starts in 1936 with Tadeus Reichstein and Ernst Laqueur who discovered corticosterone at the time Hans Selye formulated the stress concept. Today highly sophisticated technologies help to unravel the action mechanism of the glucocorticoids from gene to behaviour.

Corticosteroid hormones in the central stress response: quick-and-slow.

Recent evidence shows that corticosteroid hormones exert rapid non-genomic effects on neurons in the hypothalamus and the hippocampal CA1 region. The latter depend on classical mineralocorticoid receptors which are accessible from the outside of the plasma membrane and display a 10-fold lower affinity for corticosterone than the nuclear version involved in neuroprotection. Consequently, this 'membrane' receptor could play an important role while corticosteroid levels are high, i.

From the stalk to down under about brain glucocorticoid receptors, stress and development.

George Fink witnessed the birth of modern neuroendocrinology while examining with Geoffrey Harris the secrets of the pituitary stalk secretagogs. From thereon neuroendocrine systems were identified that linked experience and behavior with hormone secretion and action. A prime example of this integration of body and mind with the environment is provided by the corticosteroid hormones released from the adrenals in one hour pulses and after stress.

From punch to profile.

In this essay an aspect of my research is highlighted that has its roots in the mid seventies with the implementation of the 'Palkovits punch' procedure. This methodology was introduced when radiochemical and radio-immunoassay methods became sufficiently sensitive to measure key molecules for chemical neurotransmission and metabolism in minute amounts of brain tissue. For application of today's laser guided microdissection this knowledge of functional neuro-anatomy is indispensable.

Stress and the brain: from adaptation to disease.

In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation.

Stress, genes and the mechanism of programming the brain for later life.

Adverse conditions during early life are a risk factor for stress-related diseases such as depression and post-traumatic stress disorder (PTSD). How this long-term effect of early adversity occurs is not known, although evidence accumulates that the action of stress hormones is an important determinant. In rodents after a variety of experiences, even minor ones, during postnatal life permanent changes in emotional and neuroendocrine reactivity have been observed.

Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance.

Optimal regulation of the stress response is a prerequisite for adaptation, homeostasis, and health. There are two modes of operation in the stress response. First, an immediate response mode mediated by corticotrophin-releasing hormone-1 (CRH-1) receptors that organizes the behavioral, sympathetic, and hypothalamic-pituitary-adrenal (HPA) response to a stressor.

Hormones and the stressed brain.

The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action-in concert-is crucial for individual differences in coping with other individuals, which in turn depend on genetic- and experience-related factors.

Hormones, brain and stress.

The stress system orchestrates body and brain responses to the environment. This action exerted by the mediators of the stress system has two modes of operation. The immediate response mode driven by corticotropin-releasing hormone (CRH) organises via CRH-1 receptors the behavioural, sympathetic and hypothalamic-pituitary-adrenal (HPA) responses to a stressor.

Who cares for a stressed brain? The mother, the kid or both?

Data are emerging that the altered development of adrenocortical and emotional reactivity in individuals exposed perinatally to adverse events is reflected in cognitive change and that maternal care is an important determinant. However, early trauma does not cause a generalized cognitive decline at older age, but rather drives cognitive performance to the extremes, at the expense of the average performance demonstrated by normally reared individuals.

Gene x environment interaction and cognitive performance: animal studies on the role of corticosterone.

A fundamental question in the neurobiology of cognition is how stress and glucocorticoids modify learning and memory processes. Why some individuals develop cognitive deficits after stress, while other individuals improve in cognitive performance under similar adverse conditions is still unresolved. To address these questions we focus on those issues.

The Yin and Yang of nuclear receptors: symposium on nuclear receptors in brain, Oegstgeest, The Netherlands, 13-14 April 2000.

Novel aspects of nuclear receptors and their function in brain were discussed at a recent Symposium in Oegstgeest, The Netherlands. Presentations covered the diversity of these receptors, their target genes, proteins involved in transcriptional regulation, functional consequences of nuclear receptor activation and their relevance for human pathology. By elucidating the signalling pathway of nuclear receptors in brain, potential targets for therapeutic treatment of brain disorders can be identified.

Stress in the brain.

Part I (first section) reports about research in the period 1964-1976, when the seminal observations were made on which today's concept of corticosteroid action on the brain is based. These key observations concern the discovery of nuclear corticosterone receptors in the limbic brain that mediate control over neuronal circuits underlying hypothalamic-pituitary-adrenal activity and behavioural adaptation. Part II (second section) covers the period of 1977-1989.

Brain mineralocorticoid receptors and centrally regulated functions.

Mineralocorticoid receptors (MRs) expressed in limbic neurons, notably of hippocampus, retain both aldosterone and corticosterone. Basal concentrations of corticosterone already substantially occupy the limbic MR type, suggesting that in hippocampal neurons, MR activity rather than ligand bioavailability is rate limiting. The periventricular region expresses MRs involved in the control of salt homeostasis, which are aldosterone selective because of the presence of 11beta-hydroxysteroid dehydrogenase.

Brain corticosteroid receptor balance in health and disease.

In this review, we have described the function of MR and GR in hippocampal neurons. The balance in actions mediated by the two corticosteroid receptor types in these neurons appears critical for neuronal excitability, stress responsiveness, and behavioral adaptation. Dysregulation of this MR/GR balance brings neurons in a vulnerable state with consequences for regulation of the stress response and enhanced vulnerability to disease in genetically predisposed individuals.