Hypothalamo-pituitary-adrenal Axis Research Articles

Here today, not gone tomorrow: long-term effects of corticosterone

There is a growing body of evidence from across animal taxa that exposure to elevated levels of glucocorticoids during development can have profound long-term effects upon physiological and behavioral phenotypes. Several avian studies have revealed that the degree to which an individual’s hypothalamo–pituitary–adrenal (HPA) axis responds to stressful stimuli as an adult may in effect have been ‘programmed’ or set as a result of that individual’s corticosterone exposure in ovo or as a nestling. Developmental exposure to corticosterone may also have effects upon avian ‘personalities’ or coping styles, and evidence from mammalian studies suggests that these long-term effects are mediated epigenetically via altered expression of relevant DNA sequences. Although there does not appear to be a consistent across-species pattern, developmental exposure to elevated corticosterone levels may shape adult coping style with such exposure, resulting in adults that are more timid and with increased HPA axis responsiveness to stress than those individuals that were exposed to relatively little corticosterone as nestlings. Recent work in Florida Scrub-jays (Aphelocoma coerulescens) has found that baseline corticosterone levels in nestlings at 11 days post-hatch explained 84% of the variation in ‘personality’ (bold vs. timid) when those individuals were tested at approximately 7 months of age. The overall ‘personality’ scores at 7–8 months of age were based upon tests that evaluated and combined the Jays’ responses to three tests: two startle and one neophobia stimuli. Here, we present findings on some of the factors that contribute to corticosterone levels of nestling Florida Scrub-jays, both within and among broods. Our prior and continuing research, as this overview will present, suggests that maternal attentiveness at the nest and paternal provisioning are important factors that mediate nestling corticosterone levels.

The neurobiology of depression

Depressive disorder is a long term, relapsing condition associated with high levels of disability and mortality. It has a neurobiological basis and is associated with functional and structural brain abnormalities. The data discussed have been obtained mainly from meta-analyses, randomized controlled clinical trials and key review papers as well as animal studies. Genetic vulnerability and stress are key factors in its aetiopathogenesis. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis reduces hippocampal volumes and prefrontal cortex (PFC) activity in depressed patients and disrupts homeostasis within the neurocircuit of depression. Antidepressant drugs increase brain-derived neurotrophin, restoring neuronal growth and activity and modulate interactions between the neurocircuit anatomical structures. It remains to be confirmed whether structural changes in the brain are purely abnormalities in neuroplasticity and are fully reversible, whether they predate depression and whether they increase in the long term. Investigation of the molecular mechanisms mediating gene and environment interaction is a growing and potentially fruitful area of research in the neurobiology of depression. Further elucidation of the neuroanatomical and physiological connections between the limbic structures and PFC may help identify key areas to target in treatment. The role of the dysregulation of the HPA axis and identifiable stressors in the recent or remote past which are not always present in depression need further study. Prospective studies examining the interaction between changes in brain function and structure in relation to stress and identified relevant genes and how these may be influenced by antidepressant drug treatment and the long-term course of depression would help clarify their role in the pathophysiology of this disorder.

Peter Rossdale's scientific contribution to equine perinatology

Peter Rossdale's scientific contribution to equine perinatology

Psychological and physiological effects of caring for patients with treatment-resistant depression

Carers of patients with psychiatric disorders show high levels of anxiety and depression, possibly mediated through disruption of the hypothalamo-pituitary-adrenal (HPA) axis. Among carers of patients with treatment-resistant depression (TRD), we set out to determine the psychological and physiological (HPA axis) consequences of caring, and the association of these consequences with long-term outcome in patients. Thirty-five informal carers of patients with severe TRD requiring in-patient treatment were recruited and compared with 23 controls. HPA-axis activity was assessed by measuring post-awaking salivary cortisol. The Involvement Evaluation Questionnaire (IEQ) and the General Health Questionnaire-12 (GHQ-12) were administered to measure carer burden and psychiatric caseness respectively. Independent t tests were used to compare differences between carers and controls and a linear regression model was used to determine the association of post-awakening cortisol with carer status while controlling for confounding variables. Data on long-term patient outcome (12 to 83 months), measured using the Hamilton Depression Rating Scale (HAMD), were also obtained and linear regression was used to determine the association between cortisol output in carers and remission status in patients. Carers experienced high carer burden and high psychiatric caseness. Carers showed reduced cortisol output after awakening, calculated as the area under the curve with respect to ground (AUCg), which remained significant after controlling for potential confounders. In a linear regression model, non-remission in patients was associated with reduced cortisol output in carers. Caring for patients with TRD is associated with adverse psychological and physiological changes suggesting hypocortisolism post-awakening. These changes are associated with poor patient outcome.

Adrenocortical and Adipose Responses to High-Altitude-Induced, Long-Term Hypoxia in the Ovine Fetus

By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.

Medial prefrontal cortex transection enhanced stress-induced activation of sympathoadrenal system in rats

The medial prefrontal cortex (mPFC) projects to the sympathetic premotor and preganglionic neurons. Besides the well described modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis activity, the mPFC also exerts modulatory effect on the activity of the sympathoadrenal system (SAS). The aim of the present study was to find out whether interruption of the anatomical interconnections between the mPFC neurons and hypothalamic, brainstem and spinal cord structures may affect the SAS and HPA axis activities determined by the plasma catecholamines (epinephrine, EPI and norepinephrine, NE) and corticosterone (CS) levels in the rats exposed to a single immobilization (IMO) stress. The posterior transection of the mPFC was performed bilaterally by inserting a V-shaped blade into the brain of adult male Sprague Dawley rats. Sham-operated animals (controls) underwent a craniotomy only. The animals were allowed to recover for 14 days. Thereafter, the tail artery was cannulated and the animals exposed to acute IMO for 2 h. The blood samples were collected at 5, 30, 60, 120 min of the IMO. Concentrations of the plasma EPI, NE, and CS were determined by radioimmunoassay. The IMO-induced elevation of the plasma EPI levels in the mPFC-transected rats reached statistical significance at 120 min of the IMO, when compared to controls. Similarly, plasma NE levels were significantly increased at 60 and 120 min of the IMO in the mPFC-transected animals in comparison with controls. The transection had no significant effect on the plasma CS levels. The data indicate that the mPFC transection may enhance the IMO-induced SAS activity without affecting the activity of the HPA axis. We found that the mPFC may exert an inhibitory effect on the SAS activity in the stressed animals.

New Aspects of the Immunoregulation by the Hypothalamo-Pituitary-Adrenal (HPA) Axis

One of the basic neuro-immune-endocrine interaction is the hypothalamo-pituitary-adrenal axis (HPA) to harmonize immune response to inflammatory stressors. Immune defense mechanisms mediated by cytokines and other humoral factors play particularly important roles in this communication. They are also potent activators in the CNS and factors of the HPA axis, like an increased secretion of glucocorticoids (GC). They can act as major feedback regulator of the vertebrate immune response via suppression of a wide range of cytokines, as well as interferons. Increases in systemic GC levels, however, often play dual role: do not suppress all cytokines since inhibition of a particular cytokine may result in elevated production of others. External stimuli/acute stress can compromise activation of the HPA axis and activate immune processes for defense, redirecting leukocytes from the circulation to the environment/organism interface. Overall it results in release of danger-associated molecular patterns (DAMPs) to activate cells of the innate immune system, which is resolved by neural, hormonal or immune mechanisms. The chronic stress leads to chronic immune arousal and subsequent sterile, low-grade inflammation, which has been identified in most stress-related or civilized disorders in humans. The role of pituitary-gonadal axis in the activation of HPA axis results in a gender difference in HPA response to immunological challenges: e.g. can be varied during the estrus cycle, pregnancy or lactation. That corresponds to the results of recent experimental data that reveals an important role of certain neurotramsitters (such as dopamine) in immune regulation. Internal constitutional-factors of neuro-immune-endocrine interaction, such as corticotropin-releasing hormone (CRH) and its receptors (CRF-R1 and CRF-R2), melanocortin peptides, glucocorticoids or pro-inflammatory cytokines can also act as an immunoregulator, since their receptors is present in lymphoid organs, also in peripheral blood and organs that are enhanced under inflammatory conditions. In spite of series experimental data, the role of CRH and other members of its family, as well as its receptors in inflammation are still controversial. This dual role may be due to different CRF receptors and altered functionality. There are several putative mechanisms or ports of entry, in which the cytokines may affect HPA activity and CRH release. Some influences of cytokines on the HPA axis may be exerted by an indirect way. The aim of our review was to summarize and outline of key interacting agents based upon recent experimental results.

Tirotoksikozlu ve Hipotiroidili Hastalarda Tükürük Kortizol, Serum Kortizol, Plazma ACTH ve İdrar Serbest Kortizol Düzeylerinin Karşılaştırılması

Objective: Hypothalamo-pituitary-adrenal (HPA) axis is affected by thyroid hormones. The present study was designed to compare the level of salivary cortisol, serum cortisol, plasma adrenocorticotropic hormone (ACTH) and urinary free cortisol (UFC) levels in patients with subclinical and overt thyrotoxicosis and hypothyroidism. Material and Methods: We analyzed the salivary cortisol, serum cortisol, plasma ACTH and UFC levels in 123 patients with thyroid dysfunction. The patients were classified into four groups; overt thyrotoxicosis (n= 32), subclinical thyrotoxicosis (n= 29), overt hypothyroidism (n= 28) and subclinical hypothyroidism (n= 34). Results: There were no significant differences in terms of salivary cortisol, serum cortisol, plasma ACTH and UFC levels in patients with subclinical and overt thyrotoxicosi s (p> 0.05). Similarly, no significant differences could be detected in terms of salivary cortisol, serum cortisol, plasma ACTH and UFC levels in patients with subclinical and overt hypothyroidism (p> 0.05). The comparison of patients with hypothyroidism and thyrotoxicosis also did not yield any significant difference in terms of salivary cortisol, serum cortisol, plasma ACTH and UFC levels (p> 0.05). Conclusion: Similar salivary cortisol, serum cortisol, plasma ACTH and UFC levels were detected in patients with hypothyroidism and thyrotoxicosis. Thus, we may suggest that thyroid hormone status does not play a role in the HPA axis. The major limitation of this study was the absence of a healthy control group. Further studies with large numbers of patients are required to clarify the association between thyroid hormone dysfunction and glucocorticoid levels.

Neuromedins U and S involvement in the regulation of the hypothalamo–pituitary–adrenal axis

We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo–pituitary–adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expressed in the HPA axis and progress in molecular biology techniques provided new information on their actions within this system. Several lines of evidence suggest that within the HPA axis NMU and NMS act at both hypothalamic and adrenal levels. Moreover, new data suggest that NMU and NMS are involved in central and peripheral control of the stress response.

"The Lower Threshold" phenomenon in tumor cells toward endogenous digitalis-like compounds: Responsible for tumorigenesis?

Since their first discovery as potential anti-cancer drugs decades ago, there is increasing evidence that digitalis-like compounds (DLC) have anti-tumor effects. Less is known about endogenous DLC (EDLC) metabolism and regulation. As stress hormones synthesized in and secreted from the adrenal gland, they likely take part in the hypothalamo–pituitary–adrenal (HPA) axis. In a previous study, we revealed reduced EDLC concentrations in plasma and organs from immune-compromised animals and proposed that a similar situation of a deregulated HPA axis with “adrenal EDLF exhaustion” may contribute to tumorigenesis in chronic stress situations. Here, we put forward the hypothesis that a lowered EDLC response threshold of tumor cells as compared with normal cells increases the risk of tumorigenesis, especially in those individuals with reduced EDLC plasma concentrations after chronic stress exposure. We will evaluate this hypothesis by (a) summarizing the effects of different DLC concentrations on tumor as compared with normal cells and (b) reviewing some essential differences in the Na/K-ATPase of tumor as compared with normal cells (isoform pattern, pump activity, mutations of other signalosome receptors). We will conclude that (1) tumor cells, indeed, seem to have their individual “physiologic” EDLC response range that already starts at pmolar levels and (2) that individuals with markedly reduced (pmolar) EDLC plasma levels are predisposed to cancer because these EDLC concentrations will predominantly stimulate the proliferation of tumor cells. Finally, we will summarize preliminary results from our department supporting this hypothesis.

Differential regulation of gonadotropin-releasing hormone by corticotropin-releasing factor family peptides in hypothalamic N39 cells

Corticotropin-releasing factor (CRF) is involved in a variety of physiological functions including regulation of hypothalamo–pituitary–adrenal axis activity during stressful periods. Urocortins (Ucns) are known to be members of the CRF family peptides. CRF has a high affinity for CRF receptor type 1 (CRF1 receptor). Both Ucn2 and Ucn3 have very high affinity for CRF receptor type 2 (CRF2 receptor) with little or no binding affinity for the CRF1 receptor. Gonadotropin-releasing hormone (GnRH) is known to be involved in the regulation of the stress response. Gonadotropin-inhibitory hormone (GnIH) neurons interact directly with GnRH neurons, and the action of GnIH is mediated by a novel G-protein coupled receptor, Gpr147. This study aimed to explore the possible function of CRF family peptides and the regulation of GnRH mRNA in hypothalamic GnRH cells. Both mRNA and protein expression of the CRF1 receptor and CRF2 receptor were found in hypothalamic GnRH N39 cells. CRF suppressed GnRH mRNA levels via the CRF1 receptor, while Ucn2 increased the levels via the CRF2 receptor. Both CRF and Ucn2 increased Gpr147 mRNA levels. The results indicate that CRF and Ucn2 can modulate GnRH mRNA levels via each specific CRF receptor subtype. Finally, CRF suppressed GnRH protein levels, while Ucn2 increased the levels. Differential regulation of GnRH by CRF family peptides may contribute to the stress response and homeostasis in GnRH cells.

Glucocorticoid exposure of sheep at 0.7 to 0.75 gestation augments late-gestation fetal stress responses

Exposure to glucocorticoid levels inappropriately high for current maturation alters fetal hypothalamo-pituitary-adrenal axis (HPAA) development. In an established fetal sheep model, we determined whether clinical betamethasone doses used to accelerate fetal lung maturation have persistent effects on fetal HPAA hypotensive-stress responses. Pregnant ewes received saline (n = 6) or betamethasone (n = 6); 2 × 110 μg/kg body weight doses injected 24 hours apart (106/107 and 112/113 days' gestational age, term 150 days). Basal adrenocorticotropin (ACTH) and cortisol and responses to fetal hypotension were measured before and 5 days after the first course and 14 days after the second course. Basal ACTH and cortisol were similar with treatment. HPAA responses to hypotension increased after the second but not first course and ACTH/cortisol ratio increased indicating central HPAA effects. Results demonstrate latency in the emergence of fetal HPAA hyperresponsiveness following betamethasone exposure that may explain hyperresponsiveness in full-term but not preterm neonates.

Forced swim stress elicits region-specific changes in CART expression in the stress axis and stress regulatory brain areas

CART mRNA and peptides are highly expressed in the anatomical structures composing the hypothalamo-pituitary-adrenal (HPA) axis and sympatho-adrenal system. Anatomical and functional studies suggest that CART peptides may have a role in the regulation of the neuroendocrine and autonomic responses during stress. Our previous study showed that CART peptides increased significantly in the male hypothalamus and amygdala 10 min after the forced swim stress. The present study aimed to examine the effect of forced swim stress on CART peptide expression in selected brain regions, including those where CART peptide expression has not been reported before (frontal cortex, pons, medulla oblongata), as well as in endocrine glands related to stress in male Sprague Dawley rats. A total of 16 (n = 8) animals were used, including control groups. Rats were subjected to forced swim on two consecutive days, and sacrificed on the second day, 2 h after the termination of the stress procedure. Frontal cortex, pons, medulla oblongata, hypothalamus, pituitary and adrenal glands were dissected and homogenized. CART peptide expression in these tissues was measured by Western Blotting and six different CART peptide fragments were identified. Our results showed that forced swim stress elicited region-specific changes in CART peptide expression. CART was upregulated in the frontal cortex, hypothalamus, medulla oblongata and adrenal gland while there was no change in the pons and pituitary. Enhanced CART peptide fragments in these brain regions and adrenal glands may have a role in the regulation of the HPA and sympatho-adrenal axis activity during stress response.

Diuretic, anti-inflammatory, and analgesic activities of the ethanol extract from Cynoglossum lanceolatum

Ethnopharmacological relevanceCynoglossum lanceolatum Forsk. (Boraginaceae) has been used in folk medicine in china to treat acute nephritis, periodontitis, acute submandibular lymphadenitis, snake bite, etc. However, there have been no scientific reports in the modern literature on the diuretic, anti-inflammatory and analgesic effects of this plant. The objective of this study is to evaluate the above activities of the Cynoglossum lanceolatum extract (CLE) in animals. Materials and methodsThe diuretic effect of CLE was assessed in rats and rabbits. The anti-inflammatory activity was evaluated using fresh egg white-induced paw edema in rats, carrageenan-elicited paw edema in adrenalectomized rats, and dimethylbenzene-induced inflammation in mice. The analgesic action was estimated in mice using the acetic acid-induced writhing test and the hot-plate test. In addition, the acute oral toxicity of CLE was studied in mice. ResultsCLE strikingly and dose-dependently increased urine output of rats and rabbits, suppressed fresh egg white-induced paw edema in rats and carrageenan-elicited paw edema in adrenalectomized rats, reduced dimethylbenzene-induced ear edema in mice, inhibited the writhing response in mice, but did not increased reaction time of mice in the hot-plate test. No death of mice was observed when orally administered CLE up to 12g/kg. ConclusionsThese findings propose that CLE has evident diuretic, anti-inflammatory, and non-central analgesic activities. Furthermore the anti-inflammatory action does not rely on endogenetic glucocorticoids regulated by hypothalamo–pituitary–adrenal axis. On the other hand, CLE also shows a favorable safety.

The HPA axis modulates the CNS melanocortin control of liver triacylglyceride metabolism

The central melanocortin system regulates lipid metabolism in peripheral tissues such as white adipose tissue. Alterations in the activity of sympathetic nerves connecting hypothalamic cells expressing melanocortin 3/4 receptors (MC3/4R) with white adipocytes have been shown to partly mediate these effects. Interestingly, hypothalamic neurons producing corticotropin-releasing hormone and thyrotropin-releasing hormone co-express MC4R. Therefore we hypothesized that regulation of hypothalamo-pituitary adrenal (HPA) and hypothalamo-pituitary thyroid (HPT) axes activity by the central melanocortin system could contribute to its control of peripheral lipid metabolism. To test this hypothesis, we chronically infused rats intracerebroventricularly (i.c.v.) either with an MC3/4R antagonist (SHU9119), an MC3/4R agonist (MTII) or saline. Rats had been previously adrenalectomized (ADX) and supplemented daily with 1mg/kg corticosterone (s.c.), thyroidectomized (TDX) and supplemented daily with 10μg/kgL-thyroxin (s.c.), or sham operated (SO). Blockade of MC3/4R signaling with SHU9119 increased food intake and body mass, irrespective of gland surgery. The increase in body mass was accompanied by higher epididymal white adipose tissue (eWAT) weight and higher mRNA content of lipogenic enzymes in eWAT. SHU9119 infusion increased triglyceride content in the liver of SO and TDX rats, but not in those of ADX rats. Concomitantly, mRNA expression of lipogenic enzymes in liver was increased in SO and TDX, but not in ADX rats. We conclude that the HPA and HPT axes do not play an essential role in mediating central melanocortinergic effects on white adipose tissue and liver lipid metabolism. However, while basal hepatic lipid metabolism does not depend on a functional HPA axis, the induction of hepatic lipogenesis due to central melanocortin system blockade does require a functional HPA axis.

Periconceptional undernutrition suppresses cortisol response to arginine vasopressin and corticotropin-releasing hormone challenge in adult sheep offspring.

Poor maternal nutrition during pregnancy can result in increased disease risk in adult offspring. Many of these effects are proposed to be mediated via altered hypothalamo-pituitary-adrenal axis (HPAA) function, and are sex and age specific. Maternal undernutrition around the time of conception alters HPAA function in foetal and early postnatal life, but there are limited conflicting data about later effects. The aim of this study was to investigate the effect of moderate periconceptional undernutrition on HPAA function of offspring of both sexes longitudinally, from juvenile to adult life. Ewes were undernourished from 61 days before until 30 days after conception or fed ad libitum. HPAA function in offspring was assessed by arginine vasopressin plus corticotropin-releasing hormone challenge at 4, 10 and 18 months. Plasma cortisol response was lower in males than in females, and was not different between singles and twins. Periconceptional undernutrition suppressed offspring plasma cortisol but not adrenocorticotropic hormone responses. In males, this suppression was apparent by 4 months, and was more profound by 10 months, with no further change by 18 months. In females, suppression was first observed at 10 months and became more profound by 18 months. Maternal undernutrition limited to the periconceptional period has a prolonged, sex-dependent effect on adrenal function in the offspring.

Stress-evoked increases in serotonin in the auditory midbrain do not directly result from elevations in serum corticosterone

Neurochemicals such as serotonin convey information about behavioral context to sensory processing. In the auditory system, serotonin modulates the responses of neurons in the inferior colliculus (IC) to acoustic stimuli, including communication vocalizations. Levels of extracellular serotonin in the IC can change rapidly in response to stressful situations such as social challenge and limited movement. Since activation of the hypothalamo–pituitary–adrenal (HPA) axis can influence serotonin in other brain regions, we examined the relationship between serum corticosterone and serotonin release in the IC. We used voltammetry to measure extracellular serotonin in the IC of male CBA/J mice during restriction of movement, a low-intensity restraint stress. Enzyme immunoassay (EIA) was used to measure the concentration of corticosterone circulating in the blood serum as an indicator of the activation of the HPA axis. Changes in serotonin and corticosterone were also compared with behavioral performance. Restriction stress caused increases in serotonin in the IC and circulating corticosterone, and changes in behavior. Changes in serotonin and corticosterone were not correlated with each other across individuals. Individual behavioral performance was correlated with elevations in corticosterone, but not in serotonin. We further explored the relationship between physiological pathways by directly manipulating serum corticosterone. Injections of corticosterone elevated circulating levels beyond normal physiological ranges, but had no effect on serotonin in the IC. These findings suggest that, within the auditory system, serotonin is released during stressful events, but this is a correlate of behavioral arousal, rather than a direct response to elevations in serum corticosterone.

Neuroimmunological response of beluga whales (Delphinapterus leucas) to translocation and a novel social environment

This study assessed changes in phagocyte function and activation of the sympatho-adrenal medullary and hypothalamo-pituitary adrenal axes of beluga whales (Delphinapterus leucas) in response to translocation and introduction to a novel social environment. Transported belugas exhibited increases in epinephrine (E), norepinephrine (NE), and cortisol levels in response to the translocation process. In response to the introduction of the transported belugas, resident belugas exhibited an increase in E and NE but not cortisol. Moreover, the increase in E and NE shown by the transported belugas was significantly greater than the increase exhibited by the resident belugas. Resident belugas exhibited a concomitant decrease in neutrophil and monocyte phagocytosis associated with the introduction of the transported belugas. In contrast, transported belugas exhibited an attendant increase in phagocytosis and respiratory burst activity immediately following transport. Differences in phagocyte response may derive from differences in hormonal milieu, stressor modality and/or intensity, or phagocyte priming. Investigating the complex interactions between types of stressors, neuroendocrine response, and immunocompetence will lead to a better understanding of the impacts of environmental challenges, including anthropogenic perturbations, on the health of cetacean populations.

Risperidone in Ultra Low Dose Protects Against Stress in the Rodent Cold Restraint Model by Modulating Stress Pathways

The present investigation evaluates the anti-stress activity of risperidone (RIS) in the cold restraint stress (CRS) model and related stress pathways. Rats were pretreated with RIS (0.1 and 1.0 mg/kg) for 21 days before subjecting to CRS. Ultra low dose of RIS (ULD; 0.1 mg/kg) in contrast to higher dose (1.0 mg/kg) significantly reduced stress in terms of ulcer index. ULD also reversed stress-induced increase in plasma corticosterone and norepinephrine levels used as markers for the function of hypothalamo-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) respectively. ULD caused dose and brain region (hippocampus, prefrontal cortex and striatum) specific changes to stress-induced perturbations of serotonin, dopamine and its metabolites indicating modulation of brain monoaminergic system (BMS). ULD did not show any extrapyramidal side effects. Thus, the anti-stress effect ULD is probably mediated through the HPA axis, SNS and BMS. The study indicates a potential use of ULD in stress disorders.

Mimecan in pituitary corticotroph cells may regulate ACTH secretion and the HPAA

Mimecan is a protein of unknown function that is expressed in the pituitary tissues of mouse and human. In this study, we observed the function of mimecan on the proopiomelanocortin (POMC) gene in the pituitary and the hypothalamo-pituitary–adrenal axis (HPAA). Incubating pituitary corticotroph AtT-20 cells with recombinant mimecan protein stimulated adrenocorticotrophic hormone (ACTH) secretion without significantly up-regulating POMC gene expression. In addition, pituitary corticotroph AtT-20 cell corticotropin-releasing hormone receptor 1 (CRHR1) gene expression was induced by mimecan. Interestingly, long-term mimecan overexpression in corticotroph cells increased CRHR1 mRNA levels while slightly decreasing POMC mRNA expression and ACTH secretion. Using mimecan knockout mice, we found that, although the serum ACTH concentration was not significantly different between wild type and mimecan knockout mice under basal conditions, the serum ACTH level was relatively lower in mimecan knockout mice after treatment with corticotropin-releasing hormone (CRH). Meanwhile, we observed that POMC and CRHR1 gene expression decreased in primary cultured knockout mouse pituitary cells compared with wild type cells. Taken together, these data suggest that mimecan expressed in pituitary corticotroph cells mainly regulates ACTH secretion in the pituitary and coordinates the HPAA.