HPA System Research Articles

CRH, HPA system hyperactivity and antidepressant drug treatment

CRH, HPA system hyperactivity and antidepressant drug treatment

Increased basal activity of the HPA axis and renin-angiotensin system in congenital learned helpless rats exposed to stress early in development

Learned helpless behavior has been successfully bred in rats and designated as a genetic animal model of human depression and/or anxiety. Since congenital learned helpless animals have an impaired stress response in adulthood, we examined the effects of early stressors (at postnatal day 7, 14 or 21) on the hypothalamic–pituitary–adrenal axis and the renin-angiotensin system. The functioning of the hypothalamic–pituitary–adrenal axis was monitored through changes in corticosterone plasma levels in the adult animals after acute exposure to cold stress and maternal deprivation early in development. Renin-angiotensin system functioning was assessed by plasma renin activity. Unstressed congenital learned helpless rats had corticosterone levels that were similar to control animals (congenital non-learned helpless rats not stressed during development), but unstressed plasma renin activity levels of congenital learned helpless rats were lower than congenital non-learned helpless rats. There was a step-wise increase in corticosterone plasma levels in the congenital learned helpless rats with age of acute presentation of either cold stress or maternal deprivation stress (day 7, 49%; day 14, 84%; and day 21, 543% for cold stress). However, these baseline corticosterone levels were significantly lower in congenital learned helpless rats compared to congenital non-learned helpless controls. Similarly, in response to early exposure to cold stress and maternal deprivation, there was an increase in plasma renin activity levels of congenital learned helpless rats with age of presentation to either stressors. However, this increase in plasma renin activity levels was not evident in congenital non-learned helpless controls. Taken together, these results suggest that exposure to stress early in development has long-term effects on both the hypothalamic–pituitary–adrenal axis and the renin-angiotensin system, two neuroendocrine indicators of stress responsivity.

Behavioural and hormonal differences between two Lewis rat lines

Lewis (LEW) is an inbred strain of rats frequently used as an animal model of autoimmune diseases. However, there is evidence that some lines of LEW rats develop autoimmune diseases more readily than do other LEW rat lines. Because the hypothalamus–pituitary–adrenal system is involved in the pathophysiology of these diseases, we compared two LEW lines (SsNHsd and HANRijHsd) in their behavioural and neuroendocrine response to stress. In addition, we studied the psychostimulant effects of acute and repeated amphetamine in these two LEW rat lines. HAN rats were less active in the open field test and showed faster habituation of novelty-induced locomotion. The acoustic startle response was lower in HAN than in SSN rats, whereas prepulse inhibition of the startle response was greater in the HAN than in the SSN LEW subline. Moreover, HAN rats showed impaired acquisition of the two-way active avoidance response relative to SSN rats. The psychostimulant effects of acute amphetamine were smaller in HAN rats. Following repeated injections of amphetamine, behavioural sensitization to the psychostimulant effects of amphetamine was more pronounced in HAN than in SSN rats. Basal concentrations of serum corticosterone did not differ between the two rat lines. Following stress, however, HAN rats showed slightly higher corticosterone secretion than SSN rats. Our results show that two sublines of the LEW inbred strain of rats show profound behavioural differences which are only marginally paralleled by differences at the level of the HPA system.

Blunted cortisol response to a psychosocial stressor in schizophrenia

Schizophrenia is considered a neurodevelopmental disorder in which vulnerability to stress may be a contributing factor. Coping is an important psychological component of stress processing, and the hypothalamic–pituitary–adrenal system (HPA system) is one of the biological components of stress adaptation. Disturbances of either of these components may make schizophrenic patients more vulnerable to develop a psychosis under stressful circumstances. In this study, 10 schizophrenic men were compared with 10 healthy male controls in their response to a psychosocial stressor, consisting of a public-speaking task. Heart rate was monitored as a measure of autonomic arousal. HPA responses were assessed by measuring salivary cortisol. Coping skills were measured by using the Utrecht Coping List and the Ways of Coping Checklist. The stress of speaking in public increased the heart rate in both patients and controls; however, a significant cortisol response was found in the controls, but not in the schizophrenic patients. The patients used more passive and avoidant coping strategies than controls. The findings provide support for the notion that schizophrenic patients have an impaired ability to adapt, both psychologically and biologically, to their environment.

Elevated nocturnal profiles of serum leptin in patients with depression

Leptin, the protein product of the obese ( ob) gene, has been suggested to play a role in the regulation of food intake. As depressive episodes are frequently characterized by loss of appetite, reduced food intake and weight loss, altered leptin secretion might also be expected in patients with depression. Therefore, we examined nocturnal (10.00 p.m. to 7.00 a.m.) secretion of leptin, cortisol, ACTH and growth hormone (GH) in a group of 15 patients with depression and age- and sex-matched controls (age range 23–71 years). In addition, the effects of pulsatile administration of growth hormone-releasing hormone (GHRH), thought to be an endogenous antagonist of corticotropin-releasing hormone (CRH), which in turn is believed to play a critical role for the pathophysiology of depression, on nocturnal hormone secretion were assessed. Patients with depression showed a trend towards elevated nocturnal cortisol secretion ( F=3.8, p<0.05). Nocturnal serum leptin was significantly higher in patients, despite a reported weight loss ( F=8, p<0.05), but showed the same sexual dimorphism as in controls ( F=20.9, p<0.01). No significant differences were seen between patients and controls with regard to plasma GH and ACTH. GHRH treatment increased GH secretion in both patients and controls, while the other hormones were not affected. Furthermore, serum leptin was correlated with body mass index (BMI) in controls, but not in patients with depression, supporting an altered regulation of leptin secretion in depressive illness. Finally, we provide some evidence that in young female patients the normal nocturnal leptin surge is blunted. As glucocorticoids can prevent the fasting-induced decline in serum leptin, we propose that hypercortisolism in depression might counteract the reduction in leptin secretion caused by decreased food intake and weight loss. Elevated serum leptin in depression might in turn further promote CRH release, as shown in animals and, hence, contribute to HPA system hyperactivity seen in depression.

Interleukin-1-induced plasticity of hypothalamic CRH neurons and long-term stress hyperresponsiveness.

Infections and endotoxin (LPS) can affect hypothalamic CRH neurons and activate the HPA system. This can be prevented by IL-1 receptor antagonist and mimicked by IL-1. Chronic activation of the HPA system by repeated or chronic administration of IL-1 (1 week) to rats is associated with plastic changes in hypothalamic CRH neurons. Single administration IL-1 beta (5 micrograms/kg i.p.) to male Wistar or Lewis rats induced a similar form of neuroplasticity 1-3 weeks later. This is characterized by a selective increase in coproduction, costorage, and cosecretion of AVP in hypothalamic CRH neurons. Exposure of IL-1-primed rats 1-2 weeks later to foot shocks or IL-1 resulted in exaggerated ACTH and CORT responses as compared to vehicle-primed controls. Thus, rats are hyperresponsive to stressors weeks after IL-1 exposure. In IL-1-primed animals, CRH binding and CRH- and V1b receptor mRNA levels in the pituitary glands are not altered by IL-1 exposure 2 weeks earlier. We conclude that IL-1-induced, long-lasting hyperresponsiveness to stressors is primarily caused by functional alterations in the brain that may be directly related to observed plasticity of hypothalamic CRH neurons.

Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: Response to amitriptyline treatment

The effect of amitriptyline upon hypothalamic-pituitary-adrenal [HPA]-system-regulating neuropeptides (corticotropin-releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in-patients. This was followed by a 6-week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow-up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F1, 16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t-test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions.

With aging in humans the activity of the hypothalamus-pituitary-adrenal system increases and its diurnal amplitude flattens

There is compelling evidence for feedback disturbances in the hypothalamus-pituitary-adrenal system associated with human aging as assessed by challenge tests. However, reports about age-related changes in human basal activity are ambiguous and to date little is known about changes in the pulsatile features of the HPA system. To investigate these changes we studied twenty-two healthy male and eleven healthy female subjects ranging from 23 to 85 and 24 to 81 years respectively. 24-hour blood sampling with 30 minute sampling intervals was performed. From 18.00 to 24.00 hours blood was sampled every 10 minutes for analysis of pulsatile features of HPA activity. Statistical analysis revealed that age in particular had major effects upon basal HPA-system activity: there was a significant age-associated increase in minimal (p < 0.0001) and mean (p < 0.0002) cortisol plasma concentrations, but no alteration in pulsatile features. We found no age-cortisol correlation during daytime, but were able to demonstrate a strong impact of age upon cortisol plasma levels from 20.00 to 1.30 hours. The diurnal amplitude of cortisol (p < 0.0005) and ACTH (p < 0.0006), relative to the 24-hour mean of the hormones, showed an age-associated decline. Additionally, the evening cortisol quiescent period (p < 0.0001) was shortened in the elderly, suggesting increasingly impaired circadian function in aging. Our results suggest an increased basal activity and a flattened diurnal amplitude of the HPA system in the elderly.

Neonatal ACTH administration elicits long-term changes in forebrain monoamine innervation. Subsequent disruptions in hypothalamic-pituitary-adrenal and gonadal function.

The findings from this study demonstrated that the manipulation of the HPA system resulting from ACTH administration during neonatal development produces long-term, differential effects, not only on adrenocortical activity, but also on the activity and integrity of the forebrain monoamine systems. Increased concentrations of the monoamines within the forebrain regions studied at days 7 and 15, suggest a hastened maturation of these neural systems in animals neonatally treated with ACTH. The observed neurochemical alterations in these animals at one year are suggestive of an accelerated aging in the monoamine systems. A further consequence of these disturbances during development is an altered functioning of the HPG axis, as demonstrated by a delayed onset of puberty as previously reported, as well as significantly decreased proestrus plasma estradiol. Although deficits in sexual behavior also existed, it seems probable that these behavioral changes are a manifestation of altered neural systems regulating the ability to cope with a novel stimulus or situation, rather than a disruption of the "feminization" of the brain during sexual differentiation. This is in contrast to the male rat which exhibits permanent deficits in male typical sexual behavior following developmental ACTH treatment. The clinical relevance of these findings may be extensive. Perinatal exposure to events or agents that markedly increase ACTH and the corticosteroids may cause significant immediate and long-term changes in central monoamine functioning. These changes may constitute some of the most deleterious effects of stress exposure in infants and children. The alterations may be especially devastating in individuals with predispositions to stress-sensitive disorders such as anxiety, depression, and Tourette's syndrome. Finally, the use of ACTH in the treatment of infantile spasms may need to be reassessed in light of the possible long-term effects of ACTH on central monoamine functioning.

S-39-5 - Antidepressants and the HPA system

S-39-5 - Antidepressants and the HPA system

The three-way interactions between the hypothalamic-pituitary-adrenal and gonadal axes and the immune system

The stress system is controlled by brain nuclei at the hypothalamus and brainstem. These nuclei interact with each other and control the HPA axis and sympathetic nervous systems, respectively. Major inputs to the stress system arise from the cerebral cortex and subcortical systems, the sensory organs and nerves, and the endocrine and immune systems. The major peripheral effectors of the stress system are glucocorticoids and the catecholamines. Pathological hypoactivity of the stress system has been associated with atypical depression, the chronic fatigue/fibromyalgia syndromes and autoimmune inflammatory disease; hyperactivity with melancholic depression and anxiety disorders. The stress system responds in a quantitatively and qualitatively specific fashion to different stressors. A major role of the HPA axis is to restrain the immune system and prevent tissue damage. Reciprocal interactions between the HPA axis and immune system constitutes a new endocrine feedback loop that has given rise to the field of neuroendocrine immunology. Gonadal axis hormones directly, and indirectly via the HPA axis, alter the tone of the immune system and the quality and quantity of the inflammatory responses. Effects of the HPA axis on the gonadal axis are consistent with conservation and redirection of valuable resources towards homeostasis during times of stress. These complex interactions between the HPA axis, immune and the gonadal systems may prove to be fundamental in the genesis and perpetuation of autoimmune disease.

The three-way interactions between the hypothalamic-pituitary-adrenal and gonadal axes and the immune system

The stress system is controlled by brain nuclei at the hypothalamus andbrainstem. These nuclei interact with each other and control the HPA axis and sympathetic nervous systems, respectively. Major inputs to the stress system arise from the cerebral cortex and subcortical systems, the sensory organs and nerves, and the endocrine and immune systems. The major peripheral effectors of the stress system are glucocorticoids and the catecholamines. Pathological hypoactivity of the stress system has been associated with atypical depression, the chronic fatigue/fibromyalgia syndromes and autoimmune inflammatory disease; hyperactivity with melancholic depression and anxiety disorders. The stress system responds in a quantitatively and qualitatively specificfashion to different stressors. A major role of the HPA axis is to restrain the immune system and prevent tissue damage. Reciprocal interactions between the HPA axis and immune system constitutes a new endocrine feedback loop that has given rise to the field of neuroendocrine immunology. Gonadal axis hormones directly, and indirectly via the HPA axis, alter the tone of the immune system and the quality and quantity of the inflammatory responses. Effects of the HPA axis on the gonadal axis are consistent with conservation and redirection of valuable resources towards homeostasis during times of stress. These complex interactions between the HPA axis, immune and the gonadal systems may prove to be fundamental in the genesis and perpetuation of autoimmune disease.

Autism and autistic-like disorders: the hypothalamic-pituita-ry-adrenal system as a model for research.

In this article an overview is given of the differential diagnosis of autism and autistic-like disorders. The diagnosis of the so-called 'Multiple Complex Developmental Disorders' (MCDD) as a distinct entity is discussed in relation to autism and schizophrenia. Biological research and the relevance of results until recently are discussed. Finally, the importance of the hypothalamic-pituitary-adrenal system (HPA system) as a model for research is proposed. Research on the flexibility of this system may contribute in understanding the ways of stress processing in disorders like autism, MCDD and schizophrenia.

Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II

Hypothalamic-pituitary-adrenal system (HPA) function was tested in 24 patients with schizophrenia and compared to 24 age-matched healthy volunteers using the combined dexamethasone-suppression (DST/CRH) corticotropin-releasing hormone stimulation test (DST/CRH). After stimulation with CRH, the dexamethasone-pretreated patients released significantly more cortisol, but a similar amount of adrenocorticotropic hormone (ACTH) in comparison to controls. No association between DST status and degree of severity of illness and/or current medication was found. However, in comparison to unmedicated patients, those patients currently receiving antipsychotics, who were also those with a lesser degree of severity of illness, showed a decreased release of CRH-stimulated cortisol and ACTH. This study demonstrates that schizophrenic patients have a dysregulation of the HPA system as assessed with the DEX/CRH test. Overall, however, the degree of HPA-system dysfunction in schizophrenic patients seems to be of a lesser magnitude than in patients with affective disorders.

Circadian changes in the sensitivity of the corticotropin-releasing hormones-stimulated HPA system after arginine vasopressin and atrial natriuretic hormone in human male controls

In order to investigate whether modulation of the effects of corticotropin-releasing hormone (CRH) by arginine vasopressin (AVP) and atrial natriuretic hormone (ANH) is sensitive to circadian fluctuations, 12 healthy male volunteers were administered 100 micrograms hCRH during 30 min infusion of placebo, 3 IU AVP, or 150 micrograms ANH, the experiment being carried out in the morning (0800h) or in the evening (1900h). Compared with placebo, AVP significantly amplified the CRH-induced adrenocorticotropin hormone (ACTH) surge both in the morning and in the evening, whereas it enhanced cortisol secretion only in the evening. In contrast, ANH significantly reduced the ACTH surge, but only in the evening, and it reduced the cortisol surge in the morning compared to the evening. During ANH infusion plasma AVP levels were suppressed both in the morning and in the evening, pointing to a hypothalamic site of action in addition to the pituitary and adrenocortical effects. The ACTH secretion profiles were indistinguishable between morning and evening in all three experimental conditions, whereas cortisol profiles differed significantly depending on the time of day in the AVP and ANH condition, but not for placebo.

State‐independent dysregulation of the hpa system in a patient with rapid cycling: Longitudinal evaluation of dex/hcrh test status and comparison with a non‐rapid cycling major depressive control group

AbstractThe combined dexamethasone‐suppression/human corticotropin releasing hormone challenge (DEX/hCRH) test was repeatedly applied in a rapid cycling patient (RC) with bipolar illness during different affective states. The results were compared to a matched control group (n = 8) of non‐rapid cycling major depressive disorder patients in whom the DEX/hCRH test was applied at the beginning and end of a 6‐week antidepressant treatment program. RC had normal DEX suppression tests but exhibited exaggerated cortisol and ACTH responses to hCRH. Furthermore, RC's hormone responses were unaffected by the current clinical state (depressive, hypomanic, euthymic), and significantly exceeded the hormone responses of the control group at the beginning (acute) and the end (remitted) of their treatment. These findings suggest that severe and irreversible hypothalamic‐pituitary‐adrenocortical (HPA) system dysregulation may characterize rapid cycling. Depression 3:204–208 (1995). © 1995 Wiley‐Liss, Inc.

Steroid effects on central neurons and implications for psychiatric and neurological disorders.

Acute and chronic stress as well as a number of psychiatric and neurological disorders are accompanied by profound disturbances of the HPA system. These neuroendocrine alterations act back on the central nervous tissue mainly via corticosteroids-affecting glucocorticoid and mineralocorticoid receptors. The major conclusions drawn from studies probing these receptors in clinical investigations are: (1) In many such conditions central corticosteroid receptors are weakened in their capacity to curtail spontaneous and stress-elevated corticosteroid levels; (2) the combined DEX-CRH test is the best neuroendocrine tool currently available for identifying HPA abnormalities in psychiatric patients; (3) in depression the decreased corticosteroid receptor capacity in transient, and antidepressants act through reinstatement of GR and MR function probably resulting in reduced hypothalamic CRH and AVP production; (4) several neurological disorders such as MS and HIV infection are often accompanied by altered HPA function, which has therapeutic implications; and (5) various corticosteroids, their biosynthetic precursors and their metabolites have differentiable effects on the sleep EEG, which can be attributed to their mode of action; specifically, steroids such as pregnenolone and DHEA most likely are produced in glia cells and act in a paracrine fashion at neurons, thus modifying the sleep EEG in humans in a manner that suggests their potential as memory enhancers.

Endocrine and molecular responses to surgical stress

Successful adaptation to stress is a prerequisite for the survival of all organisms living in an environment in which noxious stimuli are constantly present. Higher organisms, including human beings, have developed complex mechanisms to tolerate the myriad of insults that occur to cellular constituents and organ systems after trauma with its resultant blood loss and tissue injury. Surgical stress can be conceptualized in this context, and it is therefore not surprising that human beings have developed an array of integrated stress-response axes that work in concert to return the host to a sustainable homeostatic plateau. The most important aspects of these axes are depicted in Figure 24. Surgical stress activates the higher cortical center of the brain and the spinal and baroreceptor reflexes that stimulate the hypothalamus to secrete CRH. CRH stimulates the release of ACTH from the pituitary gland, which causes the release of glucocorticoids from the adrenal cortex. Simultaneously, in a parallel fashion, surgical stress activates the sympathetic system to release catecholamines. Glucocorticoids and catecholamines are the major effectors of stress adaptation and interact at multiple levels in a synergistic fashion. They bind to specific receptors that are present in virtually every organ, although the number and affinity of a given tissue's receptor vary dramatically for individual ligands. Receptor occupancy results in short-term and long-term effects that ultimately improve the host's prospects of tolerating the stressful event. The short-term effects result in rapid actions, such as cardiovascular and metabolic responses that benefit the host in a “fight or flight” reaction. The long-term effects generally occur through alterations in gene transcription that prepare the host for, or adapt the host to, repetitive or chronic stress. Changes in the phosphorylation state of intracellular proteins are a common mode of action for both the short-term and long-term responses. These stress-responsive proteins have an enormous functional capacity: they alter enzymatic pathways, modulate hormone levels, and act as transcription factors to modify the expression of stress-responsive genes. During the last decade considerable progress has been made in explaining the complex signal transduction pathways mediating these responses. The importance of the HSPs in the host response to acute stress and their intimate association with activation of the HPA axis and sympathetic nervous system have recently been appreciated. The HSPs are likely to be induced early during organ rejection or ischemia and thus serve as diagnostic indicators. They are also known to be induced in chronic autoimmune disease states and may prove to be useful for prognostic evaluations. Finally, the ability to modulate their actions (e.g., in healing wounds) may have therapeutic benefits.

Nomenclature of Human Platelet Alloantigens: A Problem With the HPA System?

Nomenclature of Human Platelet Alloantigens: A Problem With the HPA System?

Nomenclature of human platelet alloantigens: a problem with the HPA system? [see comments

HE PAST SEVERAL YEARS have witnessed the elu- cidation of the molecular basis of a number of clini- cally relevant human platelet alloantigen systems. It would appear from the data collected from a number of different laboratories that the existence ofall ofthe offending epitopes seems to be due to the presence of single amino acid substi- tutions within the polypeptide chain of the glycoprotein (GP) that bears the alloantigenic epitope.”’ Biochemical and immunochemical characterization of allele-specific re- combinant forms of these platelet membrane GPs has shown, in those