Hypothalamic-pituitary-adrenocortical Activity Research Articles

Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system.

The effects of the tricyclic antidepressant amitriptyline on the rat hypothalamic-pituitary-adrenocortical (HPA) system were studied. The time-course experiments showed that amitriptyline, given via the drinking water (4.5 mg/kg.day), produces significant decreases (P < 0.05) in adrenal weight after 5 (-20%) and 7 weeks (-21%) of treatment. Hippocampal mineralocorticoid receptor (MR) levels were down-regulated at days 3 (-27%) and 7 (-20%), and transiently up-regulated at 2 (+40%), 5 (+74%), and 7 (+18%) weeks of treatment. Hippocampal glucocorticoid receptor (GR) levels were slightly down-regulated at days 3 (-8%) and 7 (-17%), transiently up-regulated by 26% at 5 weeks, and indistinguishable from controls after 7 weeks of treatment. MR levels were unchanged in the hypothalamus and neocortex, whereas hypothalamic GR concentrations were elevated and neocortical receptor levels were not altered. Dose-response experiments showed significant decreases in adrenal weight when rats were treated with 4.5 (-14%), 8.8 (-16%) and 14.5 (-13%) mg/kg.day antidepressant, but this applied only for the 4.5- (-14%) and 8.8- (-12%) mg/kg.day doses when the ratio of adrenal weight to body weight was considered. The dose-response relationship regarding hippocampal GR content displayed an inverted U-shaped curve, whereas this was less marked for MR levels. A dose of 4.5 mg/kg.day appeared to be optimal for the rise in MR as well as GR. Concerning the neuroendocrine implications of chronic antidepressant treatment, amitriptyline (5 weeks, 4.5 mg/kg.day) produced significant decreases in basal (ACTH, -47%; corticosterone, -31%) as well as stress (30 min novel environment)-induced plasma ACTH (-38%) and corticosterone (-57%) levels. Previous experiments have forwarded a role of limbic MR in the tonic control of basal HPA activity. Based on the present data, we hypothesize that during amitriptyline treatment a rise in limbic MR may be the initial phenomenon in a successively adjusting HPA system, as evidenced by the decreasing plasma hormone concentrations, declining adrenal size, and up-regulation of GR in particular brain regions.

Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system

The effects of the tricyclic antidepressant amitriptyline on the rat hypothalamic-pituitary-adrenocortical (HPA) system were studied. The time-course experiments showed that amitriptyline, given via the drinking water (4.5 mg/kg.day), produces significant decreases (P < 0.05) in adrenal weight after 5 (-20%) and 7 weeks (-21%) of treatment. Hippocampal mineralocorticoid receptor (MR) levels were down-regulated at days 3 (-27%) and 7 (-20%), and transiently up-regulated at 2 (+40%), 5 (+74%), and 7 (+18%) weeks of treatment. Hippocampal glucocorticoid receptor (GR) levels were slightly down-regulated at days 3 (-8%) and 7 (-17%), transiently up-regulated by 26% at 5 weeks, and indistinguishable from controls after 7 weeks of treatment. MR levels were unchanged in the hypothalamus and neocortex, whereas hypothalamic GR concentrations were elevated and neocortical receptor levels were not altered. Dose-response experiments showed significant decreases in adrenal weight when rats were treated with 4.5 (-14%), 8.8 (-16%) and 14.5 (-13%) mg/kg.day antidepressant, but this applied only for the 4.5- (-14%) and 8.8- (-12%) mg/kg.day doses when the ratio of adrenal weight to body weight was considered. The dose-response relationship regarding hippocampal GR content displayed an inverted U-shaped curve, whereas this was less marked for MR levels. A dose of 4.5 mg/kg.day appeared to be optimal for the rise in MR as well as GR. Concerning the neuroendocrine implications of chronic antidepressant treatment, amitriptyline (5 weeks, 4.5 mg/kg.day) produced significant decreases in basal (ACTH, -47%; corticosterone, -31%) as well as stress (30 min novel environment)-induced plasma ACTH (-38%) and corticosterone (-57%) levels. Previous experiments have forwarded a role of limbic MR in the tonic control of basal HPA activity. Based on the present data, we hypothesize that during amitriptyline treatment a rise in limbic MR may be the initial phenomenon in a successively adjusting HPA system, as evidenced by the decreasing plasma hormone concentrations, declining adrenal size, and up-regulation of GR in particular brain regions.

Increased neuroendocrine reactivity and decreased brain mineralocorticoid receptor-binding capacity in aged dogs.

The effects of aging on the regulation of the hypothalamus-pituitary-adrenocortical (HPA) system of the dog were investigated. For this purpose, we compared 11 healthy dogs, 11-14 yr old, with 14 young mature dogs, 18-24 months of age. Significantly higher basal HPA activity in the old dogs was indicated by their higher resting plasma concentrations of ACTH, alpha MSH, and cortisol over a 6-week period and higher cortisol excretion in 24-h urine. After stress by immobilization as well as by light electric foot shocks and after i.v. administration of 1 microgram/kg CRH, the old dogs had higher peak levels of ACTH and cortisol, but not of alpha MSH. The areas under the curve, corrected for the basal levels, for ACTH and cortisol after these challenges were also greater in the old dogs. The half-times to reach a 50% increment and a 50% decrement in the time-concentration curves of ACTH and cortisol were similar in old and young dogs. There were no differences between the old and young dogs in their response to i.v. administration of 0.01 mg/kg dexamethasone. The clearance of [14C]cortisol from plasma, as calculated in a two-compartment model, was significantly reduced in aged dogs. In the old dogs, the stress- and CRH-induced cortisol peaks were relatively higher than those of ACTH, and their adrenals weighed significantly more, suggesting chronic hyperadrenocorticotropism. Aging had a markedly different effect on the two types of corticosteroid receptors in brain and pituitary. The binding capacity of type II or glucocorticoid receptors (GRs) in the old dogs was unchanged compared with that in the young dogs in all investigated brain structures except the anterior pituitary, in which the number of GRs was increased up to 170%. Type I or mineralocorticoid receptor (MR)-binding capacity was largely decreased in the brain of old dogs. The MR levels in old dogs, expressed as a percentage of the corresponding levels in young dogs, were 34% in the dorsal hippocampus, 58% in the ventral hippocampus, 37% in the septum, and 54% in the hypothalamus. In the anterior pituitary, MR capacity was unchanged. There was no difference between Kd values of MR and GR binding in young and old dogs. We conclude that these aged dogs had elevated basal HPA activity, characterized by increased levels of basal ACTH and cortisol in plasma and of urinary cortisol excretion and by hyperreactivity of ACTH and cortisol secretion in response to challenge by stress or CRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypothalamic-pituitary-adrenocortical function in mixed and pure mania.

There is little information about hypothalamic-pituitary-adrenocortical (HPA) axis function in mania, particularly in mixed states. We therefore investigated HPA function and its relationship to clinical state in 19 hospitalized manic patients meeting Schedule for Affective Disorders and Schizophrenia - Research Diagnostic Criteria for acute manic episodes, compared patients with and without a mixed presentation, and examined correlations between HPA activity and behavior. Data were available from 13-16 patients. Behavioral and biochemical analyses were conducted during a 15-d placebo period. Patients with mania had elevated cerebrospinal fluid (CSF) and urinary free cortisol excretion compared with healthy subjects, and did not differ from depressed patients in any cortisol measures. Mixed manics had significantly higher morning plasma cortisol, postdexamethasone plasma cortisol and CSF cortisol than pure manics. Five of 7 mixed manics and 3 of 9 pure manics were dexamethasone suppression test (DST) nonsuppressors. Afternoon plasma cortisol and CSF cortisol correlated significantly with depressed mood; urinary free cortisol correlated with anxiety. None of the cortisol measures correlated with mania or agitation scores. These data suggest that increased cortisol secretion is a characteristic of the depressed state in mixed manics, although pure manics may also have increased DST nonsuppression.

Effects of acute and chronic administration of μ- and δ-opeoid agonists on the hypothalamic-pituitary-adrenocortical (HPA) axis in the rat

The control of hypothalamic-pituitary-adrenocortical (HPA) activity by opioids seems to involve stimulatory and inhibitory pathways. The purpose of the present study was to determine the acute and chronic effects of selective μ- and δ-opioid agonists, administered centrally (i.c.v.), on pituitary-adrenocortical activity in the rat. The μ-agonist DAGO ([D-Ala 2,N-MePhe 4,Glyol]enkephalin; 0.75 nmol i.c.v.) and the δ-agonist DPDPE ([D-Pen 2.5enkephalin; 194 nmol i.c.v.) both stimulated corticosterone release when administered acutely. Chronic administration of DAGO and DPDPE resulted in the development of tolerance to their neuroendocrine effects. These data suggest that both μ- and δ-opioid receptors are involved in the regulation of HPA activity under physiological conditions and during opiate abuse.

Adaptation of the Adrenocorticotropic Response to Chronic Intermittent Stress Was Altered by Intracerebroventricular Infusion of Hemicholinium-3

The role of diencephalic cholinergic neurotransmission in regulating hypothalamic-pituitary-adrenocortical (HPA) axis was investigated by means of administration of hemicholinium-3 (HC-3), a blocker of acetylcholine synthesis, in the third ventricle of hemispherectomized pigeons. Except for an early increase in ACTH and corticosterone levels following injection as a bolus of HC-3 that was ascribed to some stress-like situation, all data indicated that hypothalamic acetylcholine depletion resulted in inhibiting effects on the HPA axis. Twenty-four hours after injection of 6 micrograms of HC-3, the response to acute stress was markedly reduced in both magnitude and duration. Permanent instillation of HC-3 in the third ventricle at the rate of 0.25 microgram/h for 9 days led to lowered basal resting HPA activity and severely affected the development of adaptation to chronic intermittent stress. The anticipatory conditioned, endocrine response did not appear whereas attenuation of the poststress component was amplified. It is suggested that cholinergic mechanisms are involved in modulating the HPA function and particularly the conditioning process that takes place in the course of adaptation of the HPA response to chronic intermittent application of the same stressor.

The Hypothalamic–Pituitary–Adrenocortical Axis in Major Depression

The clinical utility of the tests of hypothalamic-pituitary-adrenocortical function discussed in this article are still to be ascertained. As with the dexamethasone suppression test, reviewed elsewhere in this issue, the application of other basal and challenge tests have furthered our understanding of the character of observed hypothalamic-pituitary-adrenocortical function in psychiatric patients. Hypothalamic-pituitary-adrenocortical physiology is complex and plastic and cannot be understood in terms of oversimplified explanations or concepts. Repeated measures over time, involving multiple assessments of axis activity, are essential in understanding the modulating effects of prior activity of the system (induced by endogenous regulatory systems or by superimposed environmental stressors) on the current function of the various levels in this closed-loop axis, where all parts influence the function of the remainder. From such an appreciation and understanding of this system can come more simplified assessments of its function, which would allow application to clinical psychiatry.

The Hypothalamic-Pituitary-Adrenocortical Axis an Major Depression

The clinical utility of the tests of hypothalamic-pituitary-adrenocortical function discussed in this article are still to be ascertained. As with the dexamethasone suppression test, reviewed elsewhere in this issue, the application of other basal and challenge tests have furthered our understanding of the character of observed hypothalamic-pituitary-adrenocortical function in psychiatric patients. Hypothalamic-pituitary-adrenocortical physiology is complex and plastic and cannot be understood in terms of oversimplified explanations or concepts. Repeated measures over time, involving multiple assessments of axis activity, are essential in understanding the modulating effects of prior activity of the system (induced by endogenous regulatory systems or by superimposed environmental stressors) on the current function of the various levels in this closed-loop axis, where all parts influence the function of the remainder. From such an appreciation and understanding of this system can come more simplified assessments of its function, which would allow application to clinical psychiatry.

Review Article: Chronobiology and Asthma. III. Timing Corticotherapy to Biological Rhythms to Optimize Treatment Goals

Synthetic corticosteroids are frequently used to manage asthma and other inflammatory diseases. The timing of such drugs (whether ingested, inhaled, or infused) in relation to body rhythms influences the magnitude of both desired and undesired effects. It is crucial that corticotherapy be correctly scheduled to the circadian system of the hypothalamic-pituitary-adrenocortical (HPA) system. The secretion of cortisol from the adrenal cortex is not constant during each 24-hour period. Instead, production of this hormone varies as a high-amplitude circadian rhythm, with most of the secretion taking place during the initial hours of the activity span and very little late in the evening and during the first half of the sleep span. Results of laboratory and human studies indicate that the timing of exogenous corticosteroids, in relation to the circadian rhythm in HPA activity, is a critical factor. For example, the optimization of corticosteroid therapy for asthmatics entails daily (or alternate-day) administrations in the morning and, if necessary, early afternoon. By timing exogenous corticosteroids early during the activity span, the risk of adrenal suppression is minimized or avoided while bronchial patency is optimally enhanced, i.e., increasing the 24-hour average forced expiratory volume in 1 second (FEV1) and reducing its nocturnal dip. Clinical findings indicate that these results are obtainable with both acute and chronic corticosteroid therapies. In contrast, splitting the daily dose of corticosteroids into several small administrations, such as at mealtimes and before bedtime, markedly increases the likelihood of adrenal suppression without achieving the desired therapeutic effect. The dosing of synthetic corticosteroids late in the afternoon or evening, whatever the route of delivery, suppresses pituitary adrenocorticotropic hormone (ACTH) production during subsequent 24-hour spans, resulting in adrenocortical inhibition. Also, morning dosing of corticosteroids over many years seems to induce less--if any--osteopenia compared to dosing at other times. The adrenal response to exogenous administration of ACTH also is circadian-rhythmic. ACTH dosing in the morning results in greatest adrenal response in terms of cortisol secretion, while dosing in the evening results in least response. Knowledge of the circadian organization of the HPA axis is necessary to optimize the effect of synthetic corticosteroids, whether they be used to treat asthma, rheumatoid arthritis or other cortico-dependent diseases, or as a substitution therapy for Addison's disease.

The role of the hypothalamic-pituitary-adrenocortical axis in post-stress induced ethanol consumption by rats

1. 1. Previous studies conducted in our laboratory demonstrated that rats given a choice between a 0.1% saccharin solution or 10% ethanol/0.1% saccharin solution and repeatedly exposed en an unpredictable basis to stressful stimuli, consumed increasing quantities of the ethanol solution following cessation of stressor presentation as compared to nonstressed control rats. 2. 2. Stressful stimuli potently activate the hypothalamic-pituitary-adrenocortical (HPA) axis, thus a systematic investigation of the HPA axis and its involvement in post-stress induced ethanol consummatory behavior was undertaken. 3. 3. Exposure to repetitive unpredictable stressful stimuli did not induce the free-choice consumption of ethanol in either hypophysectomized rats or chronic dexamethasone treated rats. 4. 4. Adrenalectomized rats exposed to chronic unpredictable stressful stimuli consumed increased quantities of ethanol following cessation of stressful stimuli in both a quantitative and qualitative manner which mirrored that of intact animals. 5. 5. Repeated intravenous administration of exogenous adrenocorticotropin (ACIH 1–39) on an unpredictable basis also induced ethanol consuming behavior, following the discontinuation of its administration. 6. 6. These results suggest that elimination of the pituitary or pharmacological antagonism of stress-induced HPA activation will prevent post-stress induced ethanol consumnmatory behavior. 7. 7. Conversely, activation of a functional hypothalamic-pituitary system or repeated administration of exogenous ACTH 1–39 will initiate ethanol consumption in rats. 8. 8. Thus, hormones secreted from the pituitary, namely ACIH, appear to play a crucial role In the post-stress Induced initiation of ethanol consuming behavior in rats.

Biogenic amine and metabolite levels in depressed patients with high versus normal hypothalamic-pituitary-adrenocortical activity

The activity of the hypothalamic-pituitary-adrenocortical (HPA) axis is often high in depressive illness. The authors studied 132 depressed patients and 80 healthy control subjects. They report a significant direct association between HPA axis activity and adrenomedullary epinephrine secretion in depressed patients. They also found that depressed patients with high HPA activity tend to have lower CSF levels of 5-hydroxyindoleacetic acid, a serotonin metabolite, and modestly lower levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of epinephrine and norepinephrine, than patients with normal HPA activity. These findings provide potentially important leads for understanding interactions of biogenic amine systems with HPA axis function.

Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man.

The first half of this manuscript is devoted to a review of the methods used and the results obtained in the published measurements of the normal responses to tests of the three main types of hypothalamic-pituitary-adrenocortical (HPA) activity in man. These are, I, basal, unstressed activity leading to appropriate levels of total daily production of cortisol in the characteristic circadian pattern; II, responses to feedback stimulation of HPA activity by metyrapone administration; and III, responses to tests of the effects of stress on the HPA system including the effects of hypoglycemia, induced fever, vasopressin administration, and ACTH injections and infusions. The advantages and shortcomings of each type of procedure are discussed. The second half of this paper describes the authors' attempts to establish the limits of normality of standard and modified methods of evaluating the HPA system. The defined limits of normality have been used to assess the HPA function in 158 patients with known or suspected disorders of the HPA system. In normal controls, halfhourly plasma cortisol determinations established the normality of circadian and postprandial fluctuations and of mean plasma cortisol concentration, 6.2 +/- 0.3 (SEM) micrograms/dl, which were closely approximated by determinations every 6 h. Metyrapone, given in a dose of 500 mg every 2 h for 24 h increased urinary 17-OHCS excretion to 10.5-32.6 mg/day or to 1.7-7.8 times basal excretion rate. Increasing rates of insulin infusion disclosed significant relationships between resulting plasma glucose and cortisol concentrations. The slopes of the delta cortisol/delta glucose responses were similar after insulin infusions (0.46 +/- 0.05) and after insulin injections, 0.15 U/kg (0.43 +/- 0.09), and were always greater than 0.20 micrograms/mg. This index provides a useful objective measure of the normality of responses to hypoglycemic stress, 0.20-0.87 micrograms/mg. Adrenocortical responses to iv infusions of ACTH (cosyntropin 0.25 mg) may be equivocal at 2 h but are clear cut at 4, 6 and 8 h. Of 158 patients in whom hypopituitarism was known or suspected because of the presence of a pituitary tumor, acromegaly, hyperprolactinemia, or clinical features, HPA function was found to be entirely normal in 88 patients and partially or severely abnormal in the remaining 70 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuroendocrine dysfunction in genetic subtypes of primary unipolar depression

Disinhibited activity of the hypothalamic-pituitary-adrenocortical (HPA) neuroendocrine system, characterized most specifically by abnormal responses to the dexamethasone suppression test (DST), is observed in 40–50% of patients with endogenous depression. The heterogeneity of endogenous depressives with respect to this neuroendocrine marker is so far unexplained. A recent report from Iowa suggested that genetic factors could account for this heterogeneity, since abnormal DST responses were found with widely differing frequencies among primary unipolar depressives subtyped by the genetic criteria of Winokur. We studied 14 patients with primary endogenous delusional unipolar depression. Abnormal DST responses were found in 79% of the entire group, and with similar frequencies among each of the Winokur subtypes. In particular, five of six patients (83%) with depression spectrum disease had abnormal DST results. This contrasts with a frequency of 4% reported by the Iowa group. We conclude that disinhibited HPA activity does occur in depression spectrum disease when a delusional endogenous depression is present. Our results and those of the Iowa study could both be consistent with a threshold model of HPA activation. The high frequency of positive DST results in delusional endogenous depressives may be determined by disinhibited central pain mechanisms. Variations in this clinical dimension, combined with variations in threshold for HPA activation by pain mechanisms, could account for the heterogeneity of DST responses among endogenous depressives.

Cholinergic influences on hypothalamic-pituitary-adrenocortical activity of stressed rats: an approach utilizing agonists and antagonists.

Cholinergic involvement in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system of male rats was evaluated using muscarinic (atropine and methacholine) and nicotine (mecamylamine and nicotine) agents, which were selected for their specificity on cholinergic receptors (ChR). They were administered either intracerebroventricularly (icv) to produce central effects, or ip to produce both central and peripheral effects, prior to subjecting the animals to either auditory or hypercapnic stress for 1 h. Plasma corticosterone was used as an index of HPA activity. The results suggest that central muscarinic ChR are involved in inhibiting HPA activity in both non-stressed and stressed animals, whereas central nicotinic ChR are excitatory during stress but inactive in the non-stressed state. Stimulation of peripheral nicotinic ChR appeared to potentiate the HPA response to hypercapnia, and to inhibit the central excitatory nicotinic ChR when the latter were activated in non-stressed and auditory stress rats. These data suggest that during auditory stress the HPA system is more dependent upon the cholinergic system for its activation than during non-stressed and hypercapnic states.

Urinary excretion of free cortisol in hypercalcaemia.

ABSTRACT Human and animal studies have uniformly demonstrated increased hypothalamic-pituitary-adrenocortical (HPA) activity during acute hypercalcaemia. The HPA-activity during chronic hypercalcaemia was investigated by means of free urinary cortisol excretion. No difference in HPA activity could be demonstrated between a hyperparathyroid hypercalcaemic and a normocalcaemic group of patients. Based on these results it is suggested that during chronic hypercalcaemia, the HPA feed back mechanism overcomes the influence of hypercalcaemia on the HPA-axis.