Central Hypothalamic-pituitary-adrenal Axis Research Articles

Review of Skin Problems Caused by Stress

Long-term exposure to social and biological/physical stressful events produces stress responses. The hypothalamic-pituitary-adrenal (HPA) axis is one of the main neuroendocrine regulatory systems in the process of stress. Recent studies have shown that skin, as a large endocrine organ, also has peripheral neuroendocrine regulatory functions similar to the central HPA axis. The skin also responds positively to stress and produces a range of symptoms. This review will introduce a series of skin apparent problems caused by stress from the perspectives of molecular biology, skin neurology, endocrinology and immunology, hoping to provide another solution for cosmetic practitioners to deal with these skin apparent problems.

Critical Illness-induced Corticosteroid Insufficiency: What It Is Not and What It Could Be.

Critical illnesses are hallmarked by increased systemic cortisol availability, a vital part of the stress response. Acute stress may trigger a life-threatening adrenal crisis when a disease of the hypothalamic–pituitary–adrenal (HPA) axis is present and not adequately treated with stress doses of hydrocortisone. Stress doses of hydrocortisone are also used to reduce high vasopressor need in patients suffering from septic shock, in the absence of adrenal insufficiency. Research performed over the last 10 years focusing on the HPA axis during critical illness has led to the insight that neither of these conditions can be labeled “critical illness–induced corticosteroid insufficiency” or CIRCI. Instead, these data suggested using the term CIRCI for a condition that may develop in prolonged critically ill patients. Indeed, when patients remain dependent on vital organ support for weeks, they are at risk of acquiring central adrenal insufficiency. The sustained increase in systemic glucocorticoid availability, mainly brought about by suppressed circulating cortisol-binding proteins and suppressed hepatic/renal cortisol metabolism, exerts negative feedback inhibition at the hypothalamus/pituitary, while high levels of other glucocorticoid receptor ligands, such as bile acids, and drugs, such as opioids, may further suppress adrenocorticotropic hormone (ACTH) secretion. The adrenal cortex, depleted from ACTH-mediated trophic signaling for weeks, may become structurally and functionally impaired, resulting in insufficient cortisol production. Such a central HPA axis suppression may be maladaptive by contributing to lingering vasopressor need and encephalopathy, hence preventing recovery. Here, we review this concept of CIRCI and we advise on how to recognize and treat this poorly understood condition.

Role of neuroimmune circuits and pruritus in psoriasis.

Psoriasis is a chronic inflammatory skin disease presenting with an array of clinical phenotypes, often associated with pruritus. Environmental and psychological stressors can exacerbate psoriasis symptoms and provoke flares. Recent studies suggest a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis in some patients with psoriasis that can result in immune dysregulation. The immune system, in turn, can communicate with the nervous system to induce, maintain or aggravate psoriasis. In the skin, peripheral sensory as well as autonomic nerves control release of inflammatory mediators from dendritic cells, mast cells, T cells or keratinocytes, thereby modulating inflammatory responses and, in case of sensory nerves, pruritus. In response to the environment or stress, cytokines, chemokines, proteases, and neuropeptides fluctuate in psoriasis and influence immune responses as well as nerve activity. Furthermore, immune cells communicate with sensory nerves which control release of cytokines, such as IL-23, that are ultimately involved in psoriasis pathogenesis. Nerves also communicate with keratinocytes to induce epidermal proliferation. Notably, in contrast to recent years the debilitating problem of pruritus in psoriasis has been increasingly appreciated. Thus, investigating neuroimmune communication in psoriasis will not only expand our knowledge about the impact of sensory nerves in inflammation and pruritus and give new insights into the impact of environmental factors activating neuroimmune circuits or of stress in psoriasis, but may also lead to novel therapies. This review summarizes the relevant literature on the role of neuroimmune circuits, stress and how the central HPA axis and its peripheral equivalent in the skin, impact psoriasis.

Adrenocorticotropin/cortisol ratio – a marker of psoriasis severity

IntroductionThe hypothalamic–pituitary–adrenal (HPA) axis plays a crucial role in systemic homeostasis and hormonal regulation of metabolic and immune functions. A similar HPA axis analog exists in the skin, where it regulates inflammation, cell proliferation and differentiation. Data regarding central HPA axis dysregulation in psoriasis are interesting but so far inconclusive.AimIn the study we attempted to determine whether central HPA axis serum components correlate with psoriasis severity.Material and methodsForty-two patients (10 women and 32 men) hospitalized at the Department of Dermatology participated in the study. None of our patients received any systemic treatment. Venous blood samples were collected at 6.00 AM. The relationship between quantitative variables and psoriasis severity based on the Psoriasis Area and Severity Index (PASI) was assessed with proc logistic in SAS 9.4.ResultsThe effect of adrenocorticotropin/cortisol ratio on the PASI group was OR 3.621 (95% confidence limits 1.217–10.775) for a 0.1 change in ratio (p = 0.02), meaning ACTH/cortisol ratio positively correlates with psoriasis severity. The effect of ACTH and cortisol on the PASI group was not statistically significant, with p-values of 0.30 and 0.23 respectively. Other inflammatory markers such as high-sensitivity C-reactive protein, neutrophils level, LDL, and total cholesterol did not show a significant correlation with PASI score.ConclusionsOur results support the role of HPA axis dysfunction in the complex pathogenesis of psoriasis, showing a positive correlation between morning ACTH/cortisol ratio and disease severity. ACTH/cortisol ratio can be regarded as a new biochemical marker of psoriasis severity worth further studies.

Involvement of the central hypothalamic-pituitary-adrenal axis in hair growth and melanogenesis among different mouse strains.

Stress has been demonstrated to play an important role in hair follicle function and the pathogenesis of some hair disorders. The central hypothalamic-pituitary-adrenal (HPA) axis is activated by stress stimuli, synthesizes and releases various components and eventually induces the pathogenesis and recurrence of peripheral diseases. Our aim is to compare the different responses under exposure of stress in hair follicle function among different mouse strains, and to detect the involvement of the central HPA axis after stress in hair follicle growth and melanogenesis. In this study, we exposed different mouse strains (C57BL/6, CBA/J, C3H/HeN, BALB/c and ICR) to a 21-day chronic restraint stress protocol and selected C57BL/6, CBA/J and BALB/c mice for further study because of their significant behavioral alterations. Then, we evaluated and compared the different responses and sensitivity to chronic restraint stress in hair follicle function and central HPA axis among the selected strains. The results showed that expression of POMC, CRF and GR mRNA and protein and serum levels of corticosterone were inhibited in response to stress. These findings suggested that chronic restraint stress may inhibit hair follicle growth and melanogenesis via regulating the key elements of the central HPA axis. In addition, the results revealed different mouse strains exhibit different responses in the central HPA axis and hair follicle after stress exposure. C57BL/6 might be the most sensitive strain among the three strains tested as well as an appropriate strain to study possible pathophysiological mechanisms by which the nervous system influences skin function and screen dermatological drugs suitable for psychotherapy. We believe the current study will provide some useful information for researchers who are interested in the bidirectional communication between the nervous and skin systems and the management of stress-induced cutaneous diseases.

Differential Responses of the HPA Axis to Mild Blast Traumatic Brain Injury in Male and Female Mice.

Traumatic brain injury (TBI) affects 10 million people worldwide, annually. TBI is linked to increased risk of psychiatric disorders. TBI, induced by explosive devices, has a unique phenotype. Over one-third of people exposed to blast-induced TBI (bTBI) have prolonged neuroendocrine deficits, shown by anterior pituitary dysfunction. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is linked to increased risk for psychiatric disorders. Not only is there limited information on how the HPA axis responds to mild bTBI (mbTBI), sex differences are understudied. We examined central and peripheral HPA axis reactivity, 7 to 10 days after mbTBI in male and female mice. Males exposed to mbTBI had increased restraint-induced serum corticosterone (CORT), but attenuated restraint-induced corticotropin-releasing factor (CRF)/c-Fos-immunoreactivity (ir) in the paraventricular nucleus of the hypothalamus (PVN). Females displayed an opposite response, with attenuated restraint-induced CORT and enhanced restraint-induced PVN CRF/c-Fos-ir. We examined potential mechanisms underlying this dysregulation and found that mbTBI did not affect pituitary (pro-opiomelanocortin and CRF receptor subtype 1) or adrenal (11β-hydroxylase, 11β-dehydrogenase 1, and melanocortin 2 receptor) gene expression. mbTBI did not alter mineralocorticoid or glucocorticoid gene expression in the PVN or relevant limbic structures. In females, but not males, mbTBI decreased c-Fos-ir in non-neuroendocrine (presumably preautonomic) CRF neurons in the PVN. Whereas we demonstrated a sex-dependent link to stress dysregulation of preautonomic neurons in females, we hypothesize that mbTBI may disrupt limbic pathways involved in HPA axis coordination in males. Overall, mbTBI altered the HPA axis in a sex-dependent manner, highlighting the importance of developing therapies to target individual strategies that males and females use to cope with mbTBI.

Bioactive forms of vitamin D selectively stimulate the skin analog of the hypothalamus-pituitary-adrenal axis in human epidermal keratinocytes

Ultraviolet radiation B stimulates both the production of vitamin D3 in the skin and the activation of the skin analog of the hypothalamic-pituitary-adrenal axis (HPA) as well as the central HPA. Since the role of vitamin D3 in the regulation of the HPA is largely unknown, we investigated the impact of 1,25(OH)2D3 and its noncalcemic analogs, 20(OH)D3 and 21(OH)pD, on the expression of the local HPA in human epidermal keratinocytes. The noncalcemic analogs showed similar efficacy to 1,25(OH)2D3 in stimulating the expression of neuropeptides, CRF, urocortins and POMC, and their receptors, CRFR1, CRFR2, MC1R, MC2R, MC3R and MC4R. Interestingly, unlike other secosteroids, the activity of 21(OH)pD did not correlate with induction of differentiation, suggesting a separate but overlapping mechanism of action. Thus, biologically active forms of vitamin D can regulate different elements of the local equivalent of the HPA with implications for the systemic HPA.

Skin under the (Spot)-Light: Cross-Talk with the Central Hypothalamic–Pituitary–Adrenal (HPA) Axis

UV radiation is among the most prevalent stressors in humans and diurnal rodents, exerting direct and indirect DNA damage, free-radical production, and interaction with specific chromophores that affects numerous biological processes. In addition to its panoply of effects, UVB (290-320 nm) radiation can specifically affect various local neuroendocrine activities by stimulating the expression of corticotropin-releasing hormone (CRH), urocortin, proopiomelanocortin (POMC), and POMC-derived peptides. Although very little is known about the interplay between the central hypothalamic-pituitary-adrenal (HPA) axis and the skin HPA axis analog, in the current issue Skobowiat and Slominski propose a novel mechanism by which exposure to UVB activates a local HPA axis in skin, which in turn activates the central HPA axis, with the requirement of a functional pituitary gland. This is the first evidence of the local HPA axis in skin contributing to the central neuroendocrine response. This raises intriguing possibilities regarding how local production of cortisol and other HPA axis molecules in skin influence overall systemic levels of cortisol and help regulate local and central HPA axes in the context of homeostasis, skin injury, and inflammatory skin disorders.

BuShenYiQi granule inhibits atopic dermatitis via improving central and skin Hypothalamic-Pituitary-Adrenal axis function.

BackgroundDysfunction of central and skin Hypothalamic-Pituitary-Adrenal (HPA) axis play important roles in pathogenesis of atopic dermatitis (AD). Our previous studies showed that several Chinese herbs could improve HPA axis function. In this study, we evaluated the anti-inflammatory effects of BuShenYiQi granule (BSYQ), a Chinese herbs formula, in AD mice and explored the effective mechanism from regulation of HPA axis.MethodsThe ovalbumin (OVA) induced AD mice model were established and treated with BSYQ. We evaluated dermatitis score and histology analysis of dorsal skin lesions, meanwhile, serum corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH) and inflammatory cytokines were determined by ELISA. The changes of CRH/proopiomelanocortin(POMC) axis elements, corresponding functional receptors and crucial genes of glucocorticosteroidogenesis in the skin were measured by quantitative real-time PCR and western blot, respectively.ResultsThe symptoms and pathological changes in skin of AD mice were significantly improved and several markers of inflammation and allergy descended obviously after BSYQ treatment. We found that AD mice had insufficient central HPA tone, but these conditions were markedly improved after BSYQ treatment. The AD mice also showed a disturbed expression of skin HPA. In lesion skin of AD mice, the mRNA and protein expressions of CRH decreased significantly, on the contrary, POMC and cytochrome P450 side-chain cleavage enzyme (CYP11A1) increased markedly, meanwhile, NR3C1 (mouse GR), CRHR2 and 11-hydroxylase type 1(CYP11B1) were reduced locally. Most of these tested indexes were improved after BSYQ treatment.ConclusionsAD mice displayed the differential expression pattern of central and skin HPA axis and BSYQ treatment significantly alleviated the symptoms of AD mice and presented anti-inflammatory and anti-allergic effects via regulating the expression of central and skin HPA axis.

Key role of CRF in the skin stress response system.

The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1α receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF→pro-opiomelanocortin→ACTH, MSH, and β-endorphin. Expression of these peptides and of CRFR-1α is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis.

Expression of Hypothalamic–Pituitary–Adrenal Axis in Common Skin Diseases: Evidence of its Association with Stress-related Disease Activity

Hypothalamic-pituitary-adrenal (HPA) axis hormones and their receptors expressed in the skin are known to function locally, but how these hormones affect the maintenance of skin homeostasis or the pathogenesis of skin diseases is not fully understood. We comprehensively reviewed the distribution and function of the central and peripheral HPA axis in various stress-related skin diseases. Previous studies have shown altered expression of central and peripheral HPA axis hormones in chronic inflammatory skin diseases and skin tumours, and that hyper-active lesional HPA axis hormones may negatively feedback to the central HPA axis and interact with some cytokines and neuropeptides, leading to symptom deterioration. This provides an evidence-based understanding of the expression of the central and peripheral HPA axis in common skin diseases and its association with disease activity.

The association of PASI scores with CRH-R1 expression in patients with psoriasis

Stress is a well-known triggering factor along with genetic predisposition on the onset and during the course of psoriasis by altering the cellular constituents of the immune system. In the skin, there is a local hypothalamic-pituitary-adrenal (HPA) axis which is the equivalent of the central HPA axis. Corticotropin-releasing hormone (CRH) is a major regulator of the HPA axis in response to stress. This study was planned to show the role of CRH receptor type 1 (CRH-R1) in pathogenesis of psoriasis, the relation with the severity of psoriasis, and interpersonal variance in skin biopsy specimens of the psoriasis patient. Study involved 46 patients with psoriasis and 20 healthy control subjects who were older than 18 years. The clinical sign and PASI scores of psoriasis patients were recorded. Immunohistochemically, expression of CRH-R1 was investigated in psoriatic lesions and control group skin. A statistically significant increase of the expression of CRH-R1 was found in the skin biopsies of psoriasis patients compared with the control group patients. In patients with psoriasis, there was a positive correlation between the expressions of CRH-R1 and PASI scores (p = 0.001, r = +0.572). In addition, a statistically significant increase of PASI scores was found in the intense-stained CRH-R1 group compared with the weakly stained CRH-R1 patient group. The present study has demonstrated that CRH-R1 could have a role in pathogenesis of the psoriasis and stress may increase the intensity of psoriasis.

Central Nervous System Lipocalin-Type Prostaglandin D2-Synthase is Correlated with Orexigenic Neuropeptides, Visceral Adiposity and Markers of the Hypothalamic-Pituitary-Adrenal Axis in Obese Humans

Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ = 0.695, P < 0.001, n = 26) and galanin (ρ = 0.651, P < 0.001) as well as visceral adipose tissue (ρ = 0.415, P = 0.035). Furthermore, CSF L-PGDS was inversely correlated with CSF leptin (ρ = -0.529, P = 0.005) and tended to correlate inversely with s.c. adipose tissue (ρ = -0.346, P = 0.084). As reported earlier, leptin treatment had no effect on weight loss and did not affect CSF L-PGDS or NPY levels compared to placebo. After weight loss, the change of CSF L-PGDS was significantly correlated with the change of CSF NPY levels (ρ = 0.604, P = 0.004, n = 21). Because of the correlation between baseline CSF L-PGDS levels and visceral adipose tissue, we examined associations with hypothalamic-pituitary-adrenal (HPA) axis components. Baseline CSF L-PGDS was correlated with corticotrophin-releasing hormone (ρ = 0.764, P < 0.001) and β-endorphin (ρ = 0.491, P < 0.001). By contrast, serum L-PGDS was not correlated with any of the measured variables either at baseline or after treatment. In summary, CSF L-PGDS was correlated with orexigenic neuropeptides, visceral fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail.

Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome

Studies of hypothalamic-pituitary-adrenal (HPA) axis function in chronic fatigue syndrome (CFS) point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone/corticotropin-releasing factor (Dex/CRF) test, in analogy with research in affective disorders. Thirty-four well-characterized female CFS patients and 25 healthy control subjects participated in the low-dose Dex/CRF test. Current major depressive episode was an exclusion criterion. History of early-life stress (ELS) was assessed with the Structured Trauma Interview. Salivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 microg CRF, p=0.038; after 100 microg CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008). CFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.

The role of corticotropin‐releasing hormone in immune‐mediated cutaneous inflammatory disease

Corticotropin-releasing hormone (CRH) coordinates the systemic stress response via hypothalamic-pituitary-adrenal (HPA) axis activation with subsequent modulation of the inflammatory response. Stress is known to affect expression of immune-mediated inflammatory diseases, many of which are associated with HPA axis abnormalities. HPA axis components including CRH and its receptors (CRH-R) exist in the skin and exhibit differential expression according to cell type, physiological fluctuations and disease states. This confirms a local functioning cutaneous HPA-like system. Peripheral CRH may exhibit proinflammatory effects. Animal studies confirm that peripheral CRH is required for induction of the inflammatory response in vivo. CRH and CRH-R are upregulated in inflammatory arthritis synovium and psoriatic skin. CRH may influence mast cell activation, direct modulation of immune cells, angiogenesis and induction of the novel orphan nuclear receptor NURR1. This transcription factor is part of the steroid/thyroid superfamily of related nuclear receptors that includes receptors for steroids, retinoids and vitamin D; ligands of these receptors are effective in treating psoriasis. The roles of CRH and NURR1 in psoriasis and inflammatory skin diseases, especially those associated with stress, remain to be elucidated. This stress may be psychological or physical. CRH, produced locally or delivered by peripheral nerves, may mediate interactions between a cutaneous HPA axis-like system and the central HPA axis--the "brain-skin axis".

Age-Related Changes in Hypothalamic-Pituitary-Adrenal Axis Activity of Male C57BL/6J Mice

As there is little known about age-related changes in the hypothalamic-pituitary-adrenal (HPA) axis of mice, we determined the daily patterns of corticosterone secretion every 2 h, together with adrenocorticotropic hormone (ACTH) release and central HPA axis markers in the morning and evening of 3-, 9- and 16-month-old male C57BL/6J mice. We observed that: (i) corticosterone secretion showed a distinct age-related circadian pattern. During the light period this was expressed by relative hypercorticism in 9-month-old mice and relative hypocorticism in 16-month-old mice. ACTH was elevated at 16 months of age; (ii) mineralocorticoid (MR) and glucocorticoid receptor (GR) mRNA expression in the hippocampus was significantly decreased in 9-month-old mice, whereas in 16-month-old mice, expression was similar to young animals. Circadian variation was modest in all age groups; (iii) the parvocellular hypothalamic paraventricular nucleus (PVN) expressed very high vasopressin mRNA, which was subject to circadian variation in 3- and 9-month-old mice. Furthermore, significant levels of MR mRNA were expressed in the PVN. In conclusion, basal HPA axis activity and expression of its central regulatory markers are age-dependent in mice. This suggests that the capacity to adjust to environmental demands is either a function of age, or depends on different dynamics of the HPA axis.

Potential role of corticrotropin‐releasing hormone in skin physiology and pathology

Previously, we have demonstrated the expression of corticotropin‐releasing hormone (CRH) and related urocortin peptides and their corresponding CRH receptors (CRH‐Rs) in the skin and identified new alternatively spliced CRH‐R1 isoforms (FASEB J 2001; 15: 1678–1693). These receptors are functional, binding CRH and related urocortin peptides and activating intracellular transduction pathways, to modify skin cell phenotype including proliferation, differentiation and immune activity. Thus, CRH‐Rs ligands can act as local growth factors and cytokines. In conjunction with the cutaneous expression of POMC peptides and their receptors as well as the expression of genes coding enzymes of corticosteroidogenic pathway, these observations also demonstrate integrated expression of the regulatory elements of the hypothalamic‐pituitary‐adrenal (HPA) axis in mammalian skin (Physiol Rev 2000; 80: 979–1020; Endocrine Rev: 21: 457–487). This cutaneous CRH/POMC system appears to be highly responsive to the common stressor ultraviolet radiation (UVR), cutaneous pathology or physiologic changes such as those associated with the hair cycle. Therefore, we have proposed that this system would be structurally analogous to the central HPA axis, with CRH, urocortin and CRH receptors playing a central role in the regulation of cutaneous reactions. Most recently, we found differential, spatiotemporal selectivity and species‐restricted expression of CRH‐Rs, suggesting that they may be evolutionary driven to adapt to the species predominant determinant of skin function: human, solar radiation and thermal energy; mice, hair cycle and production of chemical messengers.

Interaction of 5-HT and HPA axis in depression and treatment-resistant depression

Psychoendocrinology studies of depressed patients focus on the disregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Abnormalities in the HPA axis have been noted in depressed patients. Numerous data have demonstrated the existence of reciprocal interactions between the central serotonin (5-HT) system and HPA axis. These interactions are of particular relevance when considering pathological conditions, such as depression, in which modifications of both the 5-HT system and HPA axis have been evidenced. In our laboratory, we examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test and on the wet-dog shakes induced by the DOI, 5-HT2 receptor agonist with the administration of imipramine and lithium. The reduction of immobility, induced by the chronic administration of imipramine for 15 days, was blocked by treatment with ACTH for 14 days. And, chronic ACTH treatment for 14 days increased the wet-dog shake response. This effect of ACTH was not inhibited by a 14-day administration of imipramine. Accordingly, the chronic treatment of rats with ACTH may prove to be an effective model for antidepressant-treatment-resistant depression. We believe that behavioral pharmacological and molecular biological research into the interaction between the 5-HT and HPA axis will elucidate the pathogenesis of depression or antidepressant-treatment-resistant depression and the mechanism of antidepressants action.