Hypothalamic-pituitary-adrenocortical Response Research Articles

Associations Between Sleep and Cortisol Responses to Stress in Children and Adolescents: A Pilot Study

A growing body of animal and human research suggests reciprocal associations between sleep and activity of the hypothalamic pituitary adrenocortical (HPA) axis. However, few studies have examined associations between sleep and stress-induced cortisol responses in children and adolescents. This pilot study examined associations among 3 sleep parameters (sleep–wake behavior problems, daytime sleepiness, sleep quantity) and cortisol responses to stress in 31 participants ages 10 to 17 (15 males, 16 females). During a "rest" session in which participants habituated to the laboratory, daytime sleepiness, sleep–wake behavior problems, and sleep quantity were assessed using a modified Sleep Habits Survey. On a separate day, participants completed a laboratory stress session involving 3 performance stressors. Salivary cortisol was collected during baseline, stress, and recovery periods. Significant associations between participant reported sleep–wake behavior problems and cortisol reactivity were found, with greater sleep–wake behavior problems associated with decreased cortisol responses. No associations emerged between sleep quantity and cortisol responses to stress; daytime sleepiness showed a trend toward an effect on cortisol reactivity. Although preliminary, results suggest there may be important influences of sleep quality but not quantity on HPA regulation and responses to daytime stressors in children and adolescents, and further study is warranted.

Effects of prenatal betamethasone exposure on regulation of stress physiology in healthy premature infants

The objective of this study was to examine the effects of prenatal exposure to betamethasone, a corticosteroid, on postnatal stress regulation, particularly activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Effects were assessed by measuring salivary cortisol production at baseline and in response to two potentially stressful events, a heel-stick blood draw and a physical exam, in infants born at 33–34 weeks gestation. Subjects included 9 infants with antenatal betamethasone treatment (2 doses of 12 mg of betamethasone administered intramuscularly to the mother twelve hours apart) and 9 infants without such treatment. Testing took place 3–6 days after delivery. Measures of behavioral distress confirmed that both events were stressful to these premature infants. Infants with betamethasone exposure, however, failed to exhibit increases in cortisol to either stressor. In contrast, infants without betamethasone exposure displayed elevated cortisol to the heel-stick blood draw but not the physical exam. These findings suggest that antenatal corticosteroids suppress infants’ HPA response to a stressor typically encountered in a neonatal intensive care situation.

Hypothalamic-pituitary-adrenal system adaptation to detoxification in alcohol-dependent patients is affected by family history of alcoholism

Background Alcohol withdrawal profoundly affects the hypothalamic-pituitary-adrenocortical (HPA) system. We investigated whether a family history of alcoholism modulates HPA response to pharmacologic intervention during detoxification in alcohol-dependent patients. Methods Sixteen family history negative (FH-N) and 19 family history positive (FH-P) alcohol-dependent patients were admitted for withdrawal. All 35 patients were investigated 1 week after remission of withdrawal symptoms; 17 patients were also tested during acute withdrawal. Dexamethasone 1.5 mg was given orally at 11 pm, followed by 100 μg corticotropin-releasing hormone (hCRH) administered intravenously at 3 pm the following day. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were determined at 0, 30, 45, 60, and 75 min after CRH. Results During withdrawal, cortisol but not ACTH secretion was increased in patients compared with 19 control subjects matched for age and gender. After withdrawal, cortisol was normal in FH-P but still increased in FH-N patients versus control subjects, and ACTH was marginally decreased in FH-P patients only. Both hormones were increased in FH-N versus FH-P patients. Conclusions Recovery from alcohol withdrawal-induced impairment of HPA system regulation occurs earlier in FH-P than FH-N patients, indicating that the efficacy of central neuroadaptation to this ethanol-related stimulus may be related to genetic factors.

Adrenocorticotropin responses to interpersonal stress: effects of overt anger expression style and defensiveness

This study evaluated the influence of overt anger expression style and defensiveness on the hypothalamic–pituitary–adrenocortical (HPA) responses to acute psychological stress. These personality traits are thought to modulate the stress cardiovascular response and influence disease risk, however, little is known about their influence on HPA responses. Forty-six young, healthy male volunteers worked on counterbalanced extended public-speaking and mental arithmetic. The sample was dichotomitized into groups low vs. high in anger-out, using Spielberger's Anger-Expression Inventory, and in defensiveness, using the Marlowe–Crown Social Desirability Scale. Serum cortisol and adrenocorticotropic hormone (ACTH) concentrations were measured before and after performing each task. Heart rate (HR) and blood pressures (BP) were obtained continuously in 2-min intervals before, during and after the tasks. Public speaking produced greater adrenocortical and cardiovascular stress responses than mental arithmetic, and the greatest increases in ACTH occurred in subjects high in anger-out and defensiveness. These preliminary findings provide evidence that a mismatch between traits of preferred anger expression style and defensive style produces pronounced adrenocorticotropic responses during socially salient stress.

Blunted Stress Cortisol Response in Abstinent Alcoholic and Polysubstance‐Abusing Men

This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.

Dexamethasone suppression of the effects of cocaine on adrenocortical secretion in Lewis and fischer rats

There is evidence to suggest that cocaine acts centrally to enhance adrenocortical secretory activity and this effect may be associated with the reinforcing properties of this drug. Lewis (LEW) and Fischer (F344) rats are inbred strains which differ in their responses to the reinforcing effects of cocaine. Previous findings from this laboratory have demonstrated differences in the hypothalamic-pituitary-adrenocortical (HPA) responses to cocaine between these strains. To determine whether strain differences in glucocorticoid responsiveness play a role in the differential effects of cocaine on plasma corticosterone (CS) secretion in these strains, experiments were designed to suppress the HPA response to cocaine in these two rat strains. HPA activity was attenuated by central administration of the glucocorticoid agonist dexamethasone (DEX) using osmotic minipumps. A constant infusion of artificial cerebrospinal fluid or DEX (50, 100 or 500 ng/h) was delivered into the lateral ventricle of LEW and F344 rats. Four days later, the rats were challenged with cocaine HCl (0, 20 and 40 mg/kg, i.p.), and the plasma CS response 15 min later was quantified. Cocaine-induced alterations in circulating plasma CS were reduced in a dose-related manner by centrally administered DEX in both strains. Significant strain differences in the effects of DEX on the plasma CS response to cocaine were observed, suggesting that LEW rats were more sensitive to DEX suppression of HPA activity than F344 rats. DEX also produced dose-related effects on body weight in both strains and decreased adrenal weight at the highest dose in F344 rats. Blood collected on the final day of the experiment demonstrated that central infusions of DEX decreased plasma ACTH concentrations in both strains compared to control rats. These studies indicate that central administration of DEX produces a feedback inhibition of cocaine-induced glucocorticoid release and that LEW rats are more sensitive to DEX suppression than F344 rats.

Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects

This study was done to compare the effects of 6-week treatment with amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) regulation in elderly depressed patients and age-matched comparison subjects. A combined dexamethasone-suppression/CRH-stimulation (dexamethasone/CRH) test was administered before initiation of amitriptyline treatment and at the end of weeks 1, 3, and 6 of treatment. Thirty-nine depressed inpatients, mean age = 69 years, completed the study. Fourteen normal volunteers, mean age = 67 years, served as comparison subjects. In relation to the comparison subjects, the depressed patients had a profoundly abnormal HPA response, in particular an exaggerated cortisol release in the dexamethasone/CRH test. This abnormality began to disappear after 1 week of treatment with amitriptyline. In contrast, amitriptyline did not affect neuroendocrine regulation in the comparison subjects at any time during the test period. The data suggest that amitriptyline affects HPA regulation in hypercortisolemic depression only, and they raise the possibility that normalization of its feedback control is related to the antidepressive effect of amitriptyline.

Effects of various stressors on in vivo norepinephrine release in the hypothalamic paraventricular nucleus and on the pituitary-adrenocortical axis.

The hypothalamic-pituitary adrenocortical (HPA) system and sympathoneural and adrenomedullary systems are major effector systems that serve to maintain homeostasis during stress. Corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, a determinant of both HPA and autonomic responses to stress, is under the control of many neurotransmitters and neuropeptides. Norepinephrine (NE) potently stimulates CRH neurons in the PVN; however, the physiologic role of NE in stress-induced activation of the HPA is unknown. In the present study we exposed animals to various stressors (immobilization (IMMO), cold (COLD), hemorrhage (HEM), hypoglycemia elicited by insulin administration (INS), pain and tissue damage caused by formalin injection (FORM) and sc injection of physiological saline (SAL), all of which are known to activate the HPA axis. Injection of physiological saline iv was used as a control. In vivo microdialysis was used to assess stressor- and intensity-specific activation of the PVN noradrenergic system, based on measurements of NE, its intraneuronal metabolite dihydroxyphenylglycol (DHPG), and the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). Simultaneously with microdialysate collections, blood samples were obtained via catheters in the femoral artery to measure plasma ACTH and corticosterone (CORT) levels as dependent measures, to assess stress-induced activation of the HPA axis. At their highest intensities, all the stressors significantly increased levels of PVN microdialysate NE, DHPG, and DOPAC, and plasma ACTH and CORT. PVN NE levels varied across stressors, with IMMO and FORM more potent than INS, COLD, or HEM. INS and HEM evoked proportionately larger plasma ACTH responses than did IMMO, FORM, and COLD. Plasma CORT responses were largest during IMMO, FORM, and HEM. Except for COLD and HEM, there was a strong correlation of plasma ACTH levels with levels of NE, DHPG, and DOPAC in PVN microdialysate. The data suggest that, except for COLD or HEM, there is a strong positive correlation of PVN noradrenergic activation and activity of the HPA axis. With stressors such as IMMO and FORM, NE synthesis, reflected by DOPAC changes, is strongly positively correlated with activity of the HPA axis. Furthermore, the results indicate substantial stressor specificity of PVN catecholaminergic and of HPA responses to different stressors and are inconsistent with a founding tenet of Selye's stress theory, the doctrine of nonspecificity, which defines stress as the nonspecific response of the body to any demand.

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.

Comparison of Pituitary‐Adrenocortical Response to Hypoglycaemia and Surgery

The hypothalamic-pituitary-adrenocortical (HPA) responses to the hypoglycaemic stimulus and to operation (laparotomy) are compared. The studies were carried out in eight patients who were subjected to insulin-induced hypoglycaemia on the day before elective abdominal surgery. Plasma corticotrophin (ACTH) and plasma cortisol concentration increases were virtually indentical during the two procedures, which suggests that hypoglycaemia and surgical trauma are comparable stress factors and that the hypoglycaemia test is reliable in predicting the HPA responses to major surgical trauma.

CHOLINERGIC INFLUENCES ON HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL ACTIVITY OF STRESSED RATS: AN APPROACH UTILIZING CHOLINE DEFICIENT DIETS

Male rats were placed on choline (Ch) deficient diets for 3 to 14 days, without and with Ch (normal and large doses) supplemented in the drinking water, to determine whether altering the availability of Ch would affect the cholinergic system in relation to the latter's role in modulating the hypothalamic-pituitary-adrenocortical (HPA) system of non-stressed and stressed animals. The results indicate that the basal nonstressed activity of the HPA system, as assessed by adrenal and plasma corticosterone concentrations, was not affected by placing the animals on these diets for as long as 14 days. Furthermore, the in vitro production of corticosterone by these adrenal glands, in the presence or absence of adrenocorticotrophin, was similar to those observed in animals on the regular rat diet; however, the HPA responses to auditory (100 db) stress, and to a lesser extent hypercapnic (9% CO2) stress, were impaired on the Ch deficient diet (14 days), and these responses were partially corrected by supplementing the diet with Ch in the drinking water. Thus, the data suggest that altering the dietary intake of Ch may affect cholinergic activity, which in turn affects the HPA response to stressors.

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.