Hypothalamo-pituitary-adrenocortical Axis Activity Research Articles

Effects of divergent selection upon adrenocortical activity on immune traits in pig

BackgroundThe sustainability of farming and animal welfare requires the reconsideration of current selection schemes. In particular, implementation of new selection criteria related to animal health and welfare should help to produce more robust animals and to reduce anti-microbial use. The hypothalamo-pituitary-adrenocortical (HPA) axis plays a major role in metabolic regulation and adaptation processes and its activity is strongly influenced by genetic factors. A positive association between HPA axis activity and robustness was recently described. To explore whether selecting pigs upon HPA axis activity could increase their robustness, a divergent selection experiment was carried out in the Large White pig breed. This allowed the generation of low (HPAlo) and high (HPAhi) responders to adrenocorticotropic hormone administration.ResultsIn this study, we compared 23 hematologic and immune parameters of 6-week-old, HPAlo and HPAhi piglets and analysed their response to a low dose of lipopolysaccharide (LPS) two weeks later. At six weeks of age, HPAhi piglets displayed greater red blood cell and leucocyte number including CD8α+ γδ cells, cytotoxic T lymphocytes, naive T helper (Th) cells and B lymphocytes as compared to HPAlo individuals. The ability of blood cells to secrete TNFα in response to LPS ex vivo was higher for HPAhi pigs. At week eight, the inflammatory response to the LPS in vivo challenge was poorly affected by the HPA axis activity.ConclusionsDivergent selection upon HPA axis activity modulated hematologic and immune parameters in 6-week-old pigs, which may confer an advantage to HPAhi pigs at weaning. However, HPAlo and HPAhi piglets did not exhibit major differences in the parameters analysed two weeks later, i. e. in 8-week-old pigs. In conclusion, chronic exposure to high cortisol levels in HPAhi pigs does not negatively impact immunity.

Behavioral Abnormality Induced by Enhanced Hypothalamo-Pituitary-Adrenocortical Axis Activity under Dietary Zinc Deficiency and Its Usefulness as a Model.

Dietary zinc deficiency increases glucocorticoid secretion from the adrenal cortex via enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activity and induces neuropsychological symptoms, i.e., behavioral abnormality. Behavioral abnormality is due to the increase in glucocorticoid secretion rather than disturbance of brain zinc homeostasis, which occurs after the increase in glucocorticoid secretion. A major target of glucocorticoids is the hippocampus and their actions are often associated with disturbance of glutamatergic neurotransmission, which may be linked to behavioral abnormality, such as depressive symptoms and aggressive behavior under zinc deficiency. Glucocorticoid-mediated disturbance of glutamatergic neurotransmission in the hippocampus is also involved in the pathophysiology of, not only psychiatric disorders, such as depression, but also neurodegenerative disorders, e.g., Alzheimer’s disease. The evidence suggests that zinc-deficient animals are models for behavioral and psychological symptoms of dementia (BPSD), as well as depression. To understand validity to apply zinc-deficient animals as a behavioral abnormality model, this paper deals with the effect of antidepressive drugs and herbal medicines on hippocampal dysfunctions and behavioral abnormality, which are induced by enhanced HPA axis activity under dietary zinc deficiency.

Dysregulation of Hypothalamo-Pituitary-Adrenocortical Axis in Overweight Female Diabetic Subjects is Associated with Downregulation of Corticosteroid Receptors and 11β-HSD1 in the Brain.

The objective of this work was to assess hypothalamo-pituitary-adrenocortical (HPA) axis dysregulation in overweight diabetic women and investigate the possible mechanism using overweight diabetic rats. Twenty-two overweight diabetic women were recruited alongside 34 lean and 23 overweight healthy women serving as controls. Dexamethasone suppression test (0.25 mg DST) and low dose adrenocorticotropic hormone (ACTH) stimulation assay were used to evaluate the HPA axis activity. Then, high fat diet (HF) and STZ-induced diabetic rats were utilized to investigate the possible mechanism. After measurement of corticosterone circadian patterns and dexamethasone suppression levels, mRNA amounts of mineralocorticoid receptors (MR), glucocorticoid receptors (GR), and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) were determined by real time PCR at hippocampus, hypothalamus, and pituitary levels. Overweight diabetic women showed impaired HPA axis with negative feedback efficacy (suppression ratio F-DEX%: 0.52±0.06% vs. 0.49±0.06% vs. 0.14±0.08%), as well as increased adrenal cortisol secretion response to low dose ACTH stimulation. Interestingly, F-DEX% was negatively correlated with BMI (r=- 0.323, p=0.003), waist circumference (r=- 0.319, p=0.004), and HbA1c (r=- 0.334, p=0.002). Stepwise linear regression analysis showed F-DEX% was significantly related to HbA1c level (β=- 0.328, p=0.007) after adjusting for other covariates (age, BMI, waist circumference, SBP, TC, TG, and HOMA-IR). Furthermore, 11β-HSD1, MR, and GR mRNA expression levels were reduced at pituitary level while GR expression was downregulated at hippocampus level in HF and HF+STZ rats. In conclusion, hyperactive HPA axis in overweight diabetic subjects may be associated with downregulation of 11β-HSD1, MR, and GR in the brain.

Transplantation of Human Dental Pulp-Derived Stem Cells Protects against Heatstroke in Mice

Stem cells from human exfoliated deciduous tooth pulp (SHED) is a promising approach for the treatment of stroke and spinal cord injury. In this study, we investigated the therapeutic effects of SHED for the treatment of multiple organ (including brain, particularly hypothalamus) injury in heatstroke mice. ICR male mice were exposed to whole body heating (WBH; 41.2°C, relative humidity 50-55%, for 1 h) and then returned to normal room temperature (26°C). We observed that intravenous administration of SHED immediately post-WBH exhibited the following therapeutic benefits for recovery after heatstroke: (a) inhibition of WBH-induced neurologic and thermoregulatory deficits; (b) reduction of WBH-induced ischemia, hypoxia, and oxidative damage to the brain (particularly the hypothalamus); (c) attenuation of WBH-induced increased plasma levels of systemic inflammatory response molecules, such as tumor necrosis factor-α and intercellular adhesion molecule-1; (d) improvement of WBH-induced hypothalamo-pituitary-adrenocortical (HPA) axis activity (as reflected by enhanced plasma levels of both adrenocorticotrophic hormone and corticosterone); and (e) attenuation of WBH-induced multiple organ apoptosis as well as lethality. In conclusion, post-WBH treatment with SHED reduced induction of proinflammatory cytokines and oxidative radicals, enhanced plasma induction of both adrenocorticotrophic hormone and corticosterone, and improved lethality in mouse heatstroke. The protective effect of SHED may be related to a decreased inflammatory response, decreased oxidative stress, and an increased HPA axis activity following the WBH injury.

Influence of chronic stress on brain corticosteroid receptors and HPA axis activity

BackgroundDisruption of the glucocorticoid negative feedback system evoked in animals by chronic stress can be induced by downregulation of glucocorticoid receptors (GRs) in several brain regions. In the present study, the dynamics of the changes in GRs, in brain structures involved in stress reactions, prefrontal cortex, hippocampus and hypothalamus was compared with the peripheral hypothalamo-pituitary-adrenocortical (HPA) axis hormones response to chronic stress. MethodsRats were exposed to 10min restraint or restrained twice a day for 3, 7or 14 days, and 24h after the last stress session exposed to homotypic stress for 10min. Control rats were not restrained. After rapid decapitation at 0, 1, 2, and 3h after stress termination, trunk blood for plasma adrenocorticotropic hormone (ACTH) and corticosterone determinations was collected and prefrontal cortex, hippocampus and hypothalamus were excised and frozen. Plasma hormones were determined using commercially available kits and glucocorticoids and mineralocorticoids protein levels in brain structure samples were determined by western blot procedure. ResultsRestraint stress alone significantly decreased glucocorticoid receptor (GR) level in prefrontal cortex and hippocampus, and increased mineralocorticoid receptor (MR) level in hypothalamus. Prior repeated stress for 3 days significantly increased GR protein level in hippocampus and diminished that level in hypothalamus in 7 days stressed rats. Acute stress-induced strong increase in plasma ACTH and corticosterone levels decreased to control level after 1 or 2h, respectively. Prior repeated stress for 3 days markedly diminished the fall in plasma ACTH level and repeated stress for 7 days moderately deepened this decrease. Plasma ACTH level induced by homotypic stress in rats exposed to restraint for 3, 7, and 14 days did not markedly differ from its control level, whereas plasma corticosterone response was significantly diminished. The fast decrease of stress-induced high plasma ACTH and corticosterone levels was accompanied by a parallel decline of GR level only in prefrontal cortex but not in the hippocampus or hypothalamus. ConclusionsComparison of the dynamics of changes in plasma ACTH and corticosterone level with respective alterations in GR and MR in brain structures suggests that the buffering effect of repeated stress depends on the period of habituation to stress and the brain structure involved in regulation of these stress response.

Morphine Withdrawal Activates Hypothalamic-Pituitary-Adrenal Axis and Heat Shock Protein 27 in the Left Ventricle: The Role of Extracellular Signal-Regulated Kinase

The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [e.g., noradrenergic activity, induction of the hypothalamo-pituitary-adrenocortical (HPA) axis, and the expression and activation of heat shock proteins (Hsps)]. The present study investigated the role of extracellular signal-regulated protein kinase (ERK) and β-adrenoceptor on the response of stress systems to morphine withdrawal by the administration of [amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327), a selective inhibitor of ERK activation, or propranolol (a β-adrenoceptor antagonist). Dependence on morphine was induced by a 7-day subcutaneous implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by the injection of naloxone (2 mg/kg s.c.). Plasma concentrations of adrenocorticotropin and corticosterone were determined by radioimmunoassay; noradrenaline (NA) turnover in left ventricle was determined by high-performance liquid chromatography; and catechol-O-methyl transferase (COMT) and Hsp27 expression and phosphorylation at Ser82 were determined by quantitative blot immunolabeling. Morphine-withdrawn rats showed an increase of NA turnover and COMT expression in parallel with an enhancement of adrenocorticotropin and plasma corticosterone concentrations. In addition, we observed an enhancement of Hsp27 expression and phosphorylation. Pretreatment with SL327 or propranolol significantly reduced morphine withdrawal-induced increases of plasma adrenocorticotropin and Hsp27 phosphorylation at Ser82 without any changes in plasma corticosterone levels. The present findings demonstrate that morphine withdrawal is capable of inducing the activation of HPA axis in parallel with an enhancement of Hsp27 expression and Hsp27 phosphorylation at Ser82 and suggest a role for β-adrenoceptors and ERK pathways in mediating morphine-withdrawal activation of the HPA axis and cellular stress response.

Neural Regulation of the Stress Response: The Many Faces of Feedback.

The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids (GCs) are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and restore homeostasis after the immediate threat has subsided. Release of GCs is mediated by the hypothalamo-pituitary-adrenocortical (HPA) axis, driven by a neural signal originating in the paraventricular nucleus (PVN). Stress levels of GCs bind to glucocorticoid receptors (GRs) in multiple body compartments, including brain, and consequently have wide-reaching actions. For this reason, GCs serve a vital function in feedback inhibition of their own secretion. Fast, non-genomic feedback inhibition of the HPA axis is mediated at least in part by GC signaling in the PVN, acting by a cannabinoid-dependent mechanism to rapidly reduce both neural activity and GC release. Delayed feedback termination of the HPA axis response is mediated by forebrain GRs, presumably by genomic mechanisms. GCs also act in the brainstem to attenuate neuropeptidergic excitatory input to the PVN via acceleration of mRNA degradation, providing a mechanism to attenuate future responses to stressors. Thus, rather than having a single defined feedback switch, GCs work through multiple neurocircuits and signaling mechanisms to coordinate HPA axis activity to suit the overall needs of multiple body systems.

The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses

The lateral septum (LS) has been shown to have a key role in emotional processes and stress responses. However, the exact role of the LS on stress modulation is not clear, as previous lesion studies mostly used electrolytic lesions, thereby destroying the whole septal area, including medial components and/or fibers of passage. The aim of the present study was therefore, to investigate the effects of selective excitotoxic ablation of the LS on neuroendocrine and behavioral stress responses in rats. Bilateral ibotenic acid lesions of the LS increased hypothalamo–pituitary–adrenocortical (HPA) axis responses to forced swim stress indicated by enhanced plasma ACTH and corticosterone responses and higher stress-induced c-Fos-like immunoreactivity in the paraventricular hypothalamic nucleus. Moreover, LS-lesioned animals showed a more passive coping style in the forced swim test indicated by increased floating and reduced struggling/swimming behavior compared with sham-lesioned controls. Interestingly, intraseptal corticosteroid receptor blockade modulated behavioral stress coping but failed to change HPA axis stress responses. Further experiments aimed at elucidating underlying neurochemical mechanisms revealed that intraseptal administration of the selective 5-HT1A receptor antagonist WAY-100635 increased and prolonged stress-induced ACTH and corticosterone levels mimicking lesion effects, while the agonist 8-OH-DPAT suppressed HPA axis activity facilitating the inhibitory role of the LS. In addition, 8-OH-DPAT-injected animals showed increased active and decreased passive coping strategies during forced swimming suggesting antidepressant efficacy. Taken together, our data suggest that the LS promotes active stress coping behavior and is involved in a HPA-inhibitory mechanism that is at least in part mediated by septal 5-HT1A receptors and does not involve a glucocorticoid mediated feedback mechanism.

Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress

Depression is potentially life-threatening. The most important neuroendocrine abnormality in this disorder is hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. Recent findings suggest that all depression treatments may boost the neurotrophin production especially brain-derived neurotrophic factor (BDNF). Moreover, BDNF is highly involved in the regulation of HPA axis activity. The aim of this study was to determine the impact of chronic stress (restraint 3h/day for 3weeks) on animal behavior and HPA axis activity in parallel with hippocampus, hypothalamus and pituitary BDNF levels. Chronic stress induced changes in anxiety (light/dark box test) and anhedonic states (sucrose preference test) and in depressive-like behavior (forced swimming test); general locomotor activity and body temperature were modified and animal body weight gain was reduced by 17%. HPA axis activity was highly modified by chronic stress, since basal levels of mRNA and peptide hypothalamic contents in CRH and AVP and plasma concentrations in ACTH and corticosterone were significantly increased. The HPA axis response to novel acute stress was also modified in chronically stressed rats, suggesting adaptive mechanisms. Basal BDNF contents were increased in the hippocampus, hypothalamus and pituitary in chronically stressed rats and the BDNF response to novel acute stress was also modified. This multiparametric study showed that chronic restraint stress induced a depressive-like state that was sustained by mechanisms associated with BDNF regulation.

Influence of exogenous atrial natriuretic peptide on the nocturnal hypothalamic-pituitary-adrenal axis and sleep in healthy men

Atrial natriuretic peptide (ANP), originally found in the cardiac atria, is also widely distributed in the central nervous system (CNS) and has been predominantly found in the hypothalamus and the pituitary gland. Previous in vitro and in vivo studies have provided evidence for an inhibitory control of ANP at all regulatory levels of the hypothalamo-pituitary-adrenocortical (HPA) system. In vivo studies in man demonstrated that ANP inhibits stimulated pituitary-adrenal secretion during wakefulness. On the other hand, it has been reported that various neuropeptides not only influence the neuroendocrine compound of sleep, but also exert specific effects on the sleep electroencephalogram (EEG). To further characterize the role of ANP in the regulation of the nocturnal HPA axis activity and consecutive sleep regulation, we investigated sleep-endocrine effects of intravenously administered ANP in healthy men during nocturnal sleep. Eight volunteers underwent three trial conditions in random order and in a single-blind design receiving ANP infusion at the beginning of the 1st or the 2nd half of the night, or placebo. Sleep was assessed by polysomnography and blood samples were drawn in 30-min intervals for determination of adrenocorticotrophic hormone (ACTH) and cortisol during the entire night. While the ACTH and cortisol secretion during ANP infusions remained unchanged, an immediate increase of ACTH and cortisol secretion occurred after each infusion period for approximately 2h without changing basal levels and the circadian course of both hormones. Sleep EEG parameters were neither directly affected by ANP infusions nor by the following ANP-induced ACTH and cortisol secretion. The presence of such clear-cut enhancement of the pituitary-adrenal release indicates a rebound effect of ANP on HPA secretory activity and supports the idea that ANP acts as corticotropin-releasing hormone (CRH)-inhibiting factor.

Effects of Corticotropin-Releasing Factor Receptor-1 Antagonists on the Brain Stress System Responses to Morphine Withdrawal

The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone-precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP-154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A(2) cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawal-activation of brain stress neurocircuitry.

The TNF-α System: Functional Aspects in Depression, Narcolepsy and Psychopharmacology

Changes of the tumor necrosis factor-alpha (TNF-α) system have been shown to be involved in the development of psychiatric disorders and are additionally associated with changes in body weight as well as endocrine and metabolic changes in psychiatric patients. TNF-α might, for example, contribute to the pathogenesis of depression by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters and the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion. On the other hand, during an acute depressive episode, an elevated HPA axis activity may suppress TNF-α system activity, while after remission, when HPA axis activity has normalized the suppression of the TNF-α system has been shown not to be apparent any more.In narcoleptic patients, soluble TNF receptor (sTNF-R) p75 plasma levels have been shown to be elevated, suggesting a functional role of the TNF-α system in the development of this disorder.Additionally, psychotropic drugs influence the TNF-α system as well as the secretion and the effect of hormones which counteract or interact with the TNF-α system such as the intestinal hormone ghrelin. However, only preliminary studies with restricted sample sizes exist on these issues, and many open questions remain.

Neuroactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) protein levels in adult male rats

Depression is characterized by hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. In this major mood disorder, neurosteroids and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), seem to be implicated and have some antidepressant effects. BDNF is highly involved in regulation of the HPA axis, whereas neurosteroids effects have never been clearly established. In this systematic in vivo study, we showed that the principal neuroactive steroids, namely dehydroepiandrosterone (DHEA), pregnenolone (PREG) and their sulfate esters (DHEA-S and PREG-S), along with allopregnanolone (ALLO), stimulated HPA axis activity, while also modulating central BDNF contents. In detail, DHEA, DHEA-S, PREG, PREG-S and ALLO induced corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) synthesis and release at the hypothalamic level, thus enhancing plasma adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations. This stimulation of the HPA axis occurred concomitantly with BDNF modifications at the hippocampus, amygdala and hypothalamus levels. We showed that these neurosteroids induced rapid effects, probably via neurotransmitter receptors and delayed effects perhaps after metabolization in other neuroactive steroids. We highlighted that they had peripheral effects directly at the adrenal level by inducing CORT release, certainly after estrogenic metabolization. In addition, we showed that, at the dose used, only DHEA, DHEA-S and PREG-S had antidepressant effects. In conclusion, these results highly suggest that part of the HPA axis and antidepressant effects of neuroactive steroids could be mediated by BDNF, particularly at the amygdala level. They also suggest that neurosteroids effects on central BDNF could partially explain the trophic properties of these molecules.

GABAergic circuits and the stress hyporesponsive period in the rat: Ontogeny of glutamic acid decarboxylase (GAD) 67 mRNA expression in limbic–hypothalamic stress pathways

Development of the hypothalamo–pituitary–adrenocortical (HPA) axis is marked by a diminution in stress responsiveness early in the postnatal period (days 4–14 in the rat). This ‘stress hyporesponsive period’ (SHRP) is thought to be at least in part centrally mediated. To investigate central mechanisms underlying the SHRP, this study assessed expression of glutamic acid decarboxylase (GAD) 67 in key stress-regulatory regions in the forebrain following acute stress with or without prior maternal deprivation. This isoform of GAD is known to be induced by stress in the adult and is believed to be a major contributor to production of the inhibitory neurotransmitter GABA under stimulated conditions. Expression of GAD67 mRNA was increased in the hippocampus, central amygdala and dorsomedial hypothalamus in pups tested early in the SHRP (day 6) or after its conclusion (day 18). In contrast, restraint caused a down-regulation of GAD67 mRNA in these structures when tested later in the SHRP (day 12). GAD67 mRNA expression was not affected by prior maternal deprivation in these regions. Reduced GABA production in the hippocampus (interneurons) is consistent with enhanced HPA axis inhibition, whereas reduced amygdalar expression predicts impaired stress excitation. Expression of GAD67 mRNA in the bed nucleus of the stria terminalis (BST) was minimally affected by acute restraint or maternal deprivation during the SHRP. However, older animals showed down-regulation of basal expression following maternal deprivation and substantial GAD67 mRNA up-regulation in both deprived and non-deprived groups following acute restraint. In contrast, non-responsiveness of the BST during the SHRP suggests either that BST GABA circuits are not actively engaged by stressors during this period or that circuits regulating BST GAD67 production are not yet in place. Overall, the data implicate forebrain GABA circuits in inhibition of HPA axis activity during the SHRP.

Protective Effects of Endotoxin in a Rat Model of Chronic Inflammation are Accompanied By Suppressed Secretion of Pro‐Inflammatory Cytokines and Biphasic Alteration in Hypothalamo‐Pituitary‐Adrenal Axis Activity

We have previously demonstrated that Gram-negative bacterial endotoxin can exert long-term protective effects against the chronic inflammatory disease adjuvant arthritis in rats. The present study was designed to investigate the mechanisms and time-course of hypothalamo-pituitary-adrenocortical (HPA) axis activity and cytokine secretion underlying this phenomenon. Rats were injected with endotoxin (lipopolysaccharide) and blood was collected either 7 or 21 days later. Priming with endotoxin induced a biphasic alteration in secretion of adrenocorticotrophic hormone and corticosterone in response to a second injection of endotoxin, with decreased secretion observed after 7 days whereas robust secretion was observed at 21 days. Seven days following priming with endotoxin, plasma concentrations of pro-inflammatory cytokines interleukin (IL)-6 and interferon (IFN)-gamma were reduced by 90%, and tumour necrosis factor (TNF)-alpha by 70%, compared to saline-treated rats, whereas robust secretion of the anti-inflammatory cytokine IL-10 was maintained in both groups. A similar net change favouring an anti-inflammatory cytokine secretory milieu was also observed 21 days following priming with endotoxin. This study provides evidence that the long-term protective effects of endotoxin on inflammation are associated with a sustained reduction in secretion of pro-inflammatory cytokines. HPA axis hypoactivity at 7 days suggests that corticosterone is not involved in suppressing IL-6, IFN-gamma and TNF-alpha at this time point. Conversely, hypersecretion of corticosterone at 21 days may underlie synchronous suppression of IL-6 and IFN-gamma. These data provide novel insight into interactions between HPA axis activity and cytokine secretion following endotoxin priming prior to induction of inflammatory disease.

Successful Antidepressant Therapy Restores the Disturbed Interplay Between TNF-α System and HPA Axis

In depressed patients, alterations in the hypothalamo-pituitary-adrenocortical (HPA) system are the most consistent neurobiological finding. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines. We examined alterations in plasma levels of tumor necrosis factor-alpha (TNF-alpha), levels of its soluble receptors p55 (sTNF-R p55) and p75 (sTNF-R p75) as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 70 depressed inpatients without inflammation. On admission, TNF-alpha levels were inversely associated with the ACTH response to the combined dex/CRH test. Changes in TNF-alpha, sTNF-R p55, and sTNF-R p75 plasma levels from admission to discharge were positively correlated with the dex/CRH test outcome at discharge. Subgroup analysis revealed that this association was restricted to those patients achieving remission. In this subgroup, TNF-alpha levels at discharge were also positively correlated with dex/CRH test response at discharge. Our results suggest that elevated HPA axis activity in acute depression suppresses TNF-alpha system activity, while after remission, when HPA axis activity has normalized, the TNF-alpha system seems to gain influence on the HPA system.

Effects of cytokines and infections on brain neurochemistry

Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamo–pituitary–adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally non-selective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis. Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

Effect of subdiaphragmatic vagotomy on the noradrenergic and HPA axis activation induced by intraperitoneal interleukin-1 administration in rats

The vagus nerve is thought to participate in signal transduction from the immune system to the CNS. The role of the vagus in the physiological, behavioral and neurochemical responses to intraperitoneally (ip) injected interleukin-1β (IL-1β) was studied using awake subdiaphragmatically vagotomized rats. The rats were injected ip with saline and IL-1β (1 μg/rat) in random order. For the next 2–4 h, they were monitored for locomotor activity, body temperature via abdominally implanted telethermometers, hypothalamic norepinephrine (NE) secretion using in vivo microdialysis and blood sampled via intravenous catheters to determine concentrations of ACTH and corticosterone to assess hypothalamo–pituitary–adrenocortical (HPA) axis activation. Saline injections were followed by transient increases in locomotor activity, body temperature, dialysate NE and plasma concentrations of ACTH and corticosterone. These responses were not significantly altered by vagotomy. IL-1β injections resulted in short-lived increases in shivering and longer decreases in locomotor activity, as well as a delayed modest fever. IL-1β also induced prolonged elevations of hypothalamic microdialysate NE, as well as plasma ACTH and corticosterone. Similar responses were observed regardless of the order of the saline and IL-1β injections. Subdiaphragmatic vagotomy prevented the IL-1-induced increases in body temperature and the increase in dialysate NE, and markedly attenuated the increases in plasma ACTH and corticosterone. The results indicate close temporal relationships between the apparent release of NE and the increase in body temperature and the HPA activation. This together with the effects of vagotomy suggests that the activation of NE in turn increases body temperature and activates the HPA axis. However, because IL-1β induces a limited HPA activation in subdiaphragmatically vagotomized rats, the vagus nerve does not appear to be the only route by which ip IL-1β can activate the HPA axis. It is suggested that IL-1β-induced vagal activation of hypothalamic NE is the major mechanism of HPA activation at low doses of IL-1β. However, IL-1β can also exert direct effects on IL-1 receptors on cerebral blood vessels, activating cyclooxygenases and hence synthesis of prostaglandins which in turn can affect body temperature, behavior and HPA axis activation.

Mirtazapine inhibits salivary cortisol concentrations in anorexia nervosa

The antidepressant mirtazapine has been demonstrated to acutely inhibit cortisol concentrations in healthy subjects and depressed patients. Since both depressed and anorectic patients are characterized by hyperactivity of the hypothalamo-pituitary-adrenocortical (HPA) system, the clinical usefulness and the endocrinological effects of mirtazapine were investigated in anorexia nervosa (AN). Five female patients suffering from AN restricting subtype (DSM-IV criteria) were admitted to a closed ward and treated with mirtazapine for three weeks receiving 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 up to the end of the study (day 21). Besides weekly determination of clinical parameters (Body Mass Index [BMI], Hamilton Depression Rating Scale [21-HAMD]), salivary cortisol concentrations were measured before treatment (day − 1), at the beginning of treatment (day 0), after 1 week (day 7), and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 0800 up to 1400 h. Repeated-measures ANOVA revealed a significant inhibition of salivary cortisol levels during 3-week treatment with mirtazapine ( p < 0.05) which became obvious already after the first mirtazapine administration (day 0). Moreover, a trend for an increase in BMI was seen ( p = 0.063), whereas no significant changes in 21-HAMD sum scores could be demonstrated. Double-blind, placebo-controlled studies are needed to clarify the question whether the observed changes in BMI are related to the mirtazapine-induced attenuation of HPA axis activity or whether they are due to monitoring of food intake and purgative behaviour on the closed ward.

A detailed characterization of loud noise stress: Intensity analysis of hypothalamo–pituitary–adrenocortical axis and brain activation

The present studies were undertaken to help determine the putative neural circuits mediating activation of the hypothalamo–pituitary–adrenocortical (HPA) axis and the release of adrenocorticotropin hormone (ACTH) and corticosterone in response to the perceived threat of loud noise. This experiment involved placing rats in acoustic chambers overnight to avoid any handling and context changes prior to noise exposure, which was done for 30 min (between 9:00 and 10:00 am) at intensities of 80, 85, 90, 95, 100, 105, and 110 dBA in different groups ( n = 8), and included a background condition (60 dBA ambient noise). This manipulation produced a noise-intensity-related increase in plasma ACTH and corticosterone levels, with levels beginning to rise at approximately 85 dBA. c- fos mRNA induction was very low in the brains of the control and 80 dBA groups, but several brain regions displayed a noise-intensity-related induction. Of these, several forebrain regions displayed c- fos mRNA induction highly correlated ( r > 0.70) with that observed in the paraventricular hypothalamic nucleus and plasma ACTH levels. These regions included the ventrolateral septum, the anteroventral subiculum, several preoptic nuclei, the anterior bed nucleus of the stria terminalis (BNST), the anterior paraventricular nucleus of the thalamus, and the medial subdivision of the medial geniculate body. Together with prior findings with audiogenic stress, the present results suggest that either or both the anterior BNST or the lateral septum is ideally situated to trigger HPA axis activation by stimuli that are potentially threatening.