Continuous Free Cortisol Profiles in Healthy Men.

Context: In humans, approximately 95% of circulating cortisol is bound to corticosteroid-binding globulin and albumin. It is only the free fraction that is biologically active and can activate signaling pathways via glucocorticoid hormone receptors in cells. Microdialysis is a well-established technique that enables the sampling of molecules in different compartments of the body, including extracellular fluid.

Potential pleiotropic beneficial effects of adjuvant melatonergic treatment in posttraumatic stress disorder.

Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune, and autonomic system, similar to chronic stress and may play a central role in the development of stress-related disorders. Recent articles have focused on the role of sleep and circadian disruption in the pathophysiology of posttraumatic stress disorder (PTSD), suggesting that chronodisruption plays a causal role in PTSD development. Direct and indirect human and animal PTSD research suggests circadian system-linked neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology.

Glucocorticoids, epigenetic control and stress resilience.

Glucocorticoid hormones play a pivotal role in the response to stressful challenges. The surge in glucocorticoid hormone secretion after stress needs to be tightly controlled with characteristics like peak height, curvature and duration depending on the nature and severity of the challenge. This is important as chronic hyper- or hypo-responses are detrimental to health due to increasing the risk for developing a stress-related mental disorder.

GABA-independent GABAA receptor openings maintain tonic currents.

Activation of GABA(A) receptors (GABA(A)Rs) produces two forms of inhibition: phasic inhibition generated by the rapid, transient activation of synaptic GABA(A)Rs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of perisynaptic or extrasynaptic GABA(A)Rs, which can detect extracellular GABA. Such tonic GABA(A)R-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABA(A) receptor openings.

A functional role for both -aminobutyric acid (GABA) transporter-1 and GABA transporter-3 in the modulation of extracellular GABA and GABAergic tonic conductances in the rat hippocampus.

Tonic γ-aminobutyric acid (GABA)A receptor-mediated signalling controls neuronal network excitability in the hippocampus. Although the extracellular concentration of GABA (e[GABA]) is critical in determining tonic conductances, knowledge on how e[GABA] is regulated by different GABA transporters (GATs) in vivo is limited. Therefore, we studied the role of GATs in the regulation of hippocampal e[GABA] using in vivo microdialysis in freely moving rats.

Circadian and ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain.

Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the rhythms of free glucocorticoid hormones.

A rapid release of corticosteroid-binding globulin from the liver restrains the glucocorticoid hormone response to acute stress.

A strict control of glucocorticoid hormone responses to stress is essential for health. In blood, glucocorticoid hormones are for the largest part bound to corticosteroid-binding globulin (CBG), and just a minor fraction of hormone is free. Only free glucocorticoid hormone is able to exert biological effects, but little is known about its regulation during stress.

Distinct, time-dependent effects of voluntary exercise on circadian and ultradian rhythms and stress responses of free corticosterone in the rat hippocampus.

Previous work has shown that allowing rats to voluntarily exercise in a running wheel for 4 wk modifies the hypothalamic-pituitary-adrenal axis and behavioral coping responses to stress. To investigate whether long-term voluntary exercise would also affect the free, biologically active fraction of corticosterone in the brain, we conducted an in vivo microdialysis study in the hippocampus of rats. We monitored both the baseline circadian and ultradian patterns of corticosterone in hippocampus dialysates over the diurnal cycle and the responses to forced swim and novelty stress at different stages of exercise.

Corticosterone levels in the brain show a distinct ultradian rhythm but a delayed response to forced swim stress.

Circulating corticosterone levels show an ultradian rhythm resulting from the pulsatile release of glucocorticoid hormone by the adrenal cortex. Because the pattern of hormone availability to corticosteroid receptors is of functional significance, it is important to determine whether there is also a pulsatile pattern of corticosterone concentration within target tissues such as the brain. Furthermore, it is unclear whether measurements of plasma corticosterone levels accurately reflect corticosterone levels in the brain.

Stress and the brain: solving the puzzle using microdialysis.

Aberrant functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis seems to be involved in depression and anxiety. However, the mechanisms underlying the relationship between stress and mental illness are not completely resolved yet. The therapeutical efficacy of selective serotonin re-uptake inhibitors and benzodiazepines points to a key role of serotonin and gamma-aminobutyric acid (GABA) in depression and anxiety.

Water temperature determines neurochemical and behavioural responses to forced swim stress: an in vivo microdialysis and biotelemetry study in rats.

Forced swimming is a behavioural stress model increasingly used to investigate the neurocircuitry of stress responses. Although forced swim stress clearly is a psychological stressor (anxiety, panic), its physical aspects are often neglected. There are indications that behavioural and neurochemical responses to swim stress depend on the water temperature.

Voluntary exercise impacts on the rat hypothalamic-pituitary-adrenocortical axis mainly at the adrenal level.

Introduction: Evidence is accumulating that the regular performance of exercise is beneficial for stress coping. However, the hypothalamic-pituitary-adrenocortical (HPA) axis of voluntarily exercising rats has never been comprehensively investigated.

Methods: Therefore, male Sprague-Dawley rats were given access to a running wheel in their home cage for 4 weeks in which they ran 4-7 km per night.

The selective glucocorticoid receptor antagonist ORG 34116 decreases immobility time in the forced swim test and affects cAMP-responsive element-binding protein phosphorylation in rat brain.

Glucocorticoid receptor (GR) antagonists can block the retention of the immobility response in the forced swimming test. Recently, we showed that forced swimming evokes a distinct spatiotemporal pattern of cAMP-responsive element-binding protein (CREB) phosphorylation in the dentate gyrus (DG) and neocortex. In the present study, we found that chronic treatment of rats with the selective GR antagonist ORG 34116 decreased the immobility time in the forced swim test, increased baseline levels of phosphorylated CREB (P-CREB) in the DG and neocortex and affected the forced swimming-induced changes in P-CREB levels in a time- and site-specific manner.

Differential monoaminergic, neuroendocrine and behavioural responses after central administration of corticotropin-releasing factor receptor type 1 and type 2 agonists.

Corticotropin-releasing factor (CRF) mediates various aspects of the stress response. To differentiate between the roles of CRF(1) and CRF(2) receptor subtypes in monoaminergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity and behaviour we compared the effects of CRF and urocortin 1 with those of the selective CRF(2) receptor ligands urocortin 2 and urocortin 3. In vivo microdialysis in the rat hippocampus was used to assess free corticosterone, extracellular levels of serotonin (5-HT) and noradrenaline (NA), and their metabolites 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively.

Effects of exposure to a predator on behaviour and serotonergic neurotransmission in different brain regions of C57bl/6N mice.

Clinical studies and animal models have provided evidence that stress and serotonin may play a role in the aetiology of psychiatric diseases such as depression and anxiety. In addition, reciprocal interactions between stress and serotonergic neurotransmission have been demonstrated. However, the relationships between stress, serotonin and behaviour are far from completely understood.

Altered serotonergic neurotransmission but normal hypothalamic-pituitary-adrenocortical axis activity in mice chronically treated with the corticotropin-releasing hormone receptor type 1 antagonist NBI 30775.

Antagonists of the corticotropin-releasing hormone receptor type 1 (CRH-R1) are regarded as promising tools for the treatment of stress-related psychiatric disorders. Owing to the intricate relationship between CRH and serotonin (5-HT), we studied the effects of chronic oral treatment of C57Bl6/N mice with the CRH-R1 antagonist NBI 30775 (formerly known as R121919) on hippocampal serotonergic neurotransmission during basal (on 15th day of treatment) and stress (forced swimming; on 16th day of treatment) conditions by in vivo microdialysis. Given the important role of CRH in the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity and behavior, the effects of NBI 30775 on dialysate-free corticosterone levels, and on home cage and forced swimming-related behavior were also assessed.

The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.

The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight.

Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis.

We studied the effects of long-term (i.e. 4 wk) voluntary exercise on the hypothalamic-pituitary-adrenocortical (HPA) axis in male mice.

Effect of sleep and sleep deprivation on serotonergic neurotransmission in the hippocampus: a combined in vivo microdialysis/EEG study in rats.

Brainstem serotonergic neurotransmission is implicated in sleep regulation. However, the role of serotonin (5-HT) in forebrain regions in sleep-wake mechanisms is still unclear. Here, we have investigated, using a combined in vivo microdialysis/electroencephalogram method, the relationship between hippocampal 5-HT levels and sleep-wake behaviour in the rat.

Effect of chronic administration of selective glucocorticoid receptor antagonists on the rat hypothalamic-pituitary-adrenocortical axis.

The effects of the selective glucocorticoid receptor (GR) antagonists ORG 34850, ORG 34116, and ORG 34517 on the rat hypothalamic-pituitary-adrenocortical (HPA) system were investigated. To assess the potency of the compounds to occupy GR in the brain and pituitary, we applied a single acute subcutaneous (s.c.

Forced swim stress activates rat hippocampal serotonergic neurotransmission involving a corticotropin-releasing hormone receptor-dependent mechanism.

Serotonin is important for adequate coping with stress. Aberrant serotonin function is implicated in the aetiology of major depression and anxiety disorders. Dysregulation of the hypothalamic-pituitary-adrenocortical axis, involving elevated corticotropin-releasing hormone (CRH) activity, also plays a role in these stress-related illnesses.