Hypothalamic-pituitary-adrenocortical Function Research Articles

Evaluation of Neuroendocrine and Immunological Parameters in Animals Following Chronic Combined Exposure to Xenobiotics

Background: A high prevalence of chromium and benzene compounds in the environment associated with motor vehicle and industrial operations arouses interest in the study of these xenobiotics in a long-term experiment. The objective of this work was to analyze effects of a chronic combined exposure to chromium and benzene on the hypothalamic-pituitary-adrenocortical (HPA) and immune systems of male Wistar rats. Materials and methods: Eighty male Wistar rats were administered potassium dichromate and benzene with drinking water in doses equaling one maximum permissible concentration (MPC) during 135 days. The hypothalamus, pituitary gland, adrenal glands, thymus, and spleen were then studied using morphometric, histological, and electron microscopy methods. The streptavidin-biotin peroxidase method was used to determine the expression of pro-apoptotic protein p53 and anti-apoptotic protein bcl2. We also measured the body, thymus and spleen weights of animals, nucleated cell counts in the thymus, spleen, and bone marrow and evaluated the cellular composition of the spleen and bone marrow as well as spontaneous and concanavalin A-induced secretion of interferon gamma (IFN-γ), IL-4, IL-6, and IL-10 cytokines by splenocytes. Results: We established an adverse effect of the exposure on the HPA function expressed in the activation of its secretory activity, blocking the release of hypothalamic neuropeptides at the level of the neurohypophysis and leading to ultrastructural damage to the neurosecretory cells of the hypothalamus, pituitary adenocytes and adrenal cortical cells, as well as in an increase in the programmed death of thymocytes. We also observed a decrease in the thymus weight and thymocyte counts and a complex of structural and functional changes indicating the status of its accidental involution in the exposed rats. The revealed decrease in the splenocyte count in the experimental group was accompanied by an increase in the size of the white spleen pulp. An increase in the induced production of the main immunoregulatory cytokines IFN-γ and IL-4 by splenocytes was found. Conclusion: Our findings can be used to analyze impairments of the HPA and immune systems in workers with a chronic combined exposure to benzene and chromium compounds in the occupational setting.

Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling.

Interactions between genetic and environmental factors, like exposure to stress, have an important role in the pathogenesis of mood-related psychiatric disorders, such as major depressive disorder. The polyspecific organic cation transporters (OCTs) were shown previously to be sensitive to the stress hormone corticosterone in vitro, suggesting that these transporters might have a physiologic role in the response to stress. Here, we report that OCT2 is expressed in several stress-related circuits in the brain and along the hypothalamic-pituitary-adrenocortical (HPA) axis. Genetic deletion of OCT2 in mice enhanced hormonal response to acute stress and impaired HPA function without altering adrenal sensitivity to adrenocorticotropic hormone (ACTH). As a consequence, OCT2(-/-) mice were potently more sensitive to the action of unpredictable chronic mild stress (UCMS) on depression-related behaviors involving self-care, spatial memory, social interaction and stress-sensitive spontaneous behavior. The functional state of the glycogen synthase kinase-3β (GSK3β) signaling pathway, highly responsive to acute stress, was altered in the hippocampus of OCT2(-/-) mice. In vivo pharmacology and western blot experiments argue for increased serotonin tonus as a main mechanism for impaired GSK3β signaling in OCT2(-/-) mice brain during acute response to stress. Our findings identify OCT2 as an important determinant of the response to stress in the brain, suggesting that in humans OCT2 mutations or blockade by certain therapeutic drugs could interfere with HPA axis function and enhance vulnerability to repeated adverse events leading to stress-related disorders.

Effects of Antenatal Corticosteroids on the Hypothalamic-Pituitary-Adrenocortical Axis of the Fetus and Newborn

The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuroendocrine pathway that modulates the stress response. The glucocorticoid, cortisol, is the principal end product of the HPA axis in humans and plays a fundamental role in maintaining homeostasis and in fetal maturation and development. Antenatal administration of synthetic glucocorticoids (GCs) accelerates fetal lung maturation and has significantly decreased neonatal mortality and morbidity in infants born before 34 weeks of gestation. Exposure to excess levels of endogenous GCs and exogenous GCs (betamethasone and dexamethasone) has been shown to alter the normal development trajectory. The development and regulation of the fetal HPA axis is discussed and the experimental animal evidence presented suggests long-term adverse consequences of altered HPA function. The clinical data in infants exposed to GCs also suggest altered HPA axis function over the short term. The longer-term consequences of antenatal GC exposure on HPA axis function and subtler neurodevelopmental outcomes including adaptation to stress, cognition, behavior, and the cardiovascular and immune responses are poorly understood. Emerging clinical strategies and interventions may help in the selection of mothers at risk for preterm delivery who would benefit from existing or future formulations of antenatal GCs with a reduction in the associated risk to the fetus and newborn. Detailed longitudinal long-term follow-up of those infants exposed to synthetic GCs are needed.

Adoption as an intervention for institutionally reared children: HPA functioning and developmental status

Institutional care, particularly when experienced early in life, is associated with delays in social and emotional development that often persist years after adoption. It has been hypothesized that compromise of the hypothalamic–pituitary–adrenocortical (HPA) axis due to adverse condition in institutions is a mediator of later emotional and behavioral problems. The first goal of our project was to investigate whether improvements in the social and emotional environment are associated with changes in HPA axis function. The second goal was to explore whether HPA alterations related to early social adversity were associated with more compromised general development and social and emotional functioning post adoption. Children adopted from Eastern European orphanages (N=76, mean age was 17 months, SD=5) were followed as part of an ongoing longitudinal study. Data, including diurnal cortisol patterns, were collected at two time points: baseline (within one month of adoption) and follow-up (six months later). Cortisol values were averaged over two days of saliva sampling after wake-up and before bedtime. We found that morning cortisol values increased between the baseline assessment (M=0.27μg/dl, SD=0.13) and follow-up (M=0.33μg/dl, SD=0.20), t(76)=−2.1, p<0.05. HPA functioning was not associated with general developmental level at either the initial or six months post-adoption assessments. However, dysregulation of the HPA axis (i.e., flatter diurnal pattern) at follow-up was associated with more behavioral and emotional problems. Overall, these results suggest that investigating specific physiological mechanisms is important in identifying children at risk for persistent social and emotional problems and in understanding the long-term consequences of early adversity. Future work should investigate whether disturbance in the HPA system is a heightened risk for long-term negative developmental outcomes.

Adrenocortical responsiveness to infusions of physiological doses of ACTH is not altered in posttraumatic stress disorder

Early studies of posttraumatic stress disorder (PTSD) reported that abnormal function of the hypothalamic–pituitary–adrenocortical (HPA) system was associated with the disorder. However, subsequent studies attempting to identify a specific aspect of HPA dysfunction that characterizes PTSD have been marked by considerable inconsistency of results. A facet of HPA regulation that has been considered but not definitively investigated is the possibility that the responsiveness of the adrenal cortex to physiological concentrations of adrenocorticotropin (ACTH) is diminished in PTSD. Relationships between PTSD and the adrenal androgen dehydroepiandrosterone (DHEA) have also been postulated. In this study we investigated the magnitude and time course of changes in concentrations of plasma cortisol and DHEA in response to bolus infusions of physiological doses of ACTH 1–24 in PTSD patients and control subjects. We found no evidence for PTSD-related alterations in cortisol or DHEA secretion in response to stimulation by low doses of ACTH and conclude that adrenocortical responsiveness is normal in PTSD. Results from this and other studies suggest that the occurrence of defects in HPA function in PTSD may be specific responses to particular combinations of trauma type, genetic susceptibility, and individual history.

Neuroendocrine and sleep regulation as predictors of illness course and therapy in depression

Background and Aims:In depression, changes in EEG sleep measures are well documented findings. However, the predictive value of these alterations for treatment and long-term course of depression still warrants clarification. Therefore, we examined whether the previous course of depression, treatment response during antidepressant therapy, and the long-term outcome in follow-up are associated with sleep regulation. Since the hypothalamic-pituitary-adrenocortical (HPA) system may play a crucial role in depression's neurobiology, we evaluated HPA system function as well.Methods:15 patients (4 men, 11 women; age 43–59) with depression were enrolled in the study. HPA system assessment using the combined DEX/CRH test and sleep EEG studies were conducted at baseline, after a 6 week antidepressant treatment period (trimipramine), and at follow-up, i.e., after 2-10 years.Results:The previous clinical course, i.e., the number of episodes until baseline, correlated significantly with EEG sleep measures i.e. sleep continuity values, slow wave sleep (SWS) and REM latency.During treatment sleep continuity values improved and the correlation with the previous long-term course disappeared. The correlation with SWS persisted. The only sleep EEG marker at baseline predictive for treatment response was REM latency.In the prospective long-term outcome SWS and REM density variables were related to the occurrence of recurrences. These sleep EEG markers correlated closely with HPA system regulation.Conclusions:The long-term outcome of depression is related to the sleep EEG pattern: SWS and REM density measures may reflect predictive markers for the long-term course. These markers are associated with HPA system regulation.

Longitudinal neuroendocrine changes assessed by dexamethasone/CRH and growth hormone releasing hormone tests in psychotic depression

Although psychotic depression has been reported to exhibit a greater degree of dysregulation of hypothalamic-pituitary-adrenocortical (HPA) function than non-psychotic depression, little is known concerning hypothalamic-pituitary-somatotropic (HPS) function in psychotic depression and how neuroendocrine function changes after treatment. To investigate the longitudinal changes in HPA and HPS system function in psychotic depression, we performed repeated dexamethasone/corticotropin releasing hormone (DEX/CRH) tests and growth hormone (GH) releasing hormone (GHRH) tests in inpatients with major depressive disorder. The psychotic depression group exhibited greater elevation of ACTH responses to the DEX/CRH test and stronger decreases in GH responses to the GHRH test than the non-psychotic depression group at admission. At discharge, the neuroendocrine responses to the DEX/CRH test of the psychotic depression group were still stronger than those of the non-psychotic depression group, though there were no significant differences in severity of depression between the groups. There were significant longitudinal changes in neuroendocrine responses to the DEX/CRH test between admission and discharge. The psychotic depression group exhibited increased GH responses to GHRH at discharge compared with those at admission, whereas no significant longitudinal change in GH response was found in the non-psychotic depression group. Consequently, there were no significant differences in GH responses to GHRH between the psychotic and non-psychotic depression groups at discharge. The results of GHRH test showed no significant relationships with severity of depression except psychotic features and the results of the DEX/CRH test. Our findings suggest that the HPS axis may be associated with psychotic features rather than general severity of depression. Further longitudinal studies are needed to clarify the role of HPS function in psychotic depression and whether sustained dysregulation of HPA function in psychotic depression is associated with a poor outcome after discharge.

If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans.

The notion that chronic stress fosters disease by activating the hypothalamic-pituitary-adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed that much of the variability is attributable to stressor and person features. Timing is an especially critical element, as hormonal activity is elevated at stressor onset but reduces as time passes. Stressors that threaten physical integrity, involve trauma, and are uncontrollable elicit a high, flat diurnal profile of cortisol secretion. Finally, HPA activity is shaped by a person's response to the situation; it increases with subjective distress but is lower in persons with posttraumatic stress disorder.

Regulation of the Hypothalamic–Pituitary–Adrenocortical System in Patients with Panic Disorder

Anxiety and depressive disorders are among the most common psychiatric disorders with a high number of hospital admissions and a lifetime prevalence of up to 25%. So far, the pathophysiological mechanisms for anxiety disorders remain to be found. Preclinical studies suggest that changes in hypothalamic-pituitary-adrenocortical (HPA) system function are causally related to the expression of anxiety-related behavior. The findings on HPA system function in patients with anxiety disorders are, however, heterogeneous. Both hypo- and hyperresponsiveness of HPA response in various anxiety disorders under different experimental conditions were found. In order to characterize putative case/control differences in HPA system function, we performed a Dex-CRH test, a widely used test to pick up changes in HPA system regulation with high sensitivity, in 30 patients with panic disorder, 35 patients with major depressive episode and in 30 controls individually matched for ethnicity, age and gender. The results indicate a similar dysregulation of the HPA system response in the Dex-CRH test in both patient groups. This finding further underlines the hypothesis that both, depression and panic disorder, share impaired HPA system regulation, supporting the notion that the impairment is involved in the pathophysiology of these clinical conditions. However, differences in the suppression effects and psychopathological correlation patterns between depressed and panic patients suggest different biological mechanisms of HPA system dysregulation in both disorders.

Cortisol secretion patterns in addiction and addiction risk

Addiction to alcohol or nicotine involves altered functioning of the brain's motivational systems. Altered functioning of the hypothalamic–pituitary–adrenocortical (HPA) axis may hold clues to the nature of the motivational changes accompanying addiction and vulnerability to addiction. Alcohol and nicotine show at least three forms of interaction with HPA functioning. Acute intake of both substances causes stress-like cortisol responses. Their persistent use may dysregulate the HPA. Finally, the risk for dependence and for relapse after quitting may be associated with deficient cortisol reactivity to a variety of stressors. The HPA is regulated at the hypothalamus by diurnal and metabolic signals, but during acute emotional states, its regulation is superseded by signals from the limbic system and prefrontal cortex. This top–down organization makes the HPA responsive to inputs that reflect motivational processes. The HPA is accordingly a useful system for studying psychophysiological reactivity in persons who may vary in cognitive, emotional, and behavioral tendencies associated with addiction and risk for addiction. Chronic, heavy intake of alcohol and nicotine may cause modifications in these frontal–limbic interactions and may account for HPA response differences in seen in alcoholics and smokers. In addition, preexisting alterations in frontal–limbic interactions with the HPA may reflect addiction-proneness, as shown in studies of offspring of alcohol- and drug-abusing parents. Continuing research on the relationship between HPA function, stress responsivity, and the addictions may yield insights into how the brain's motivational systems support addictions and risk for addictions.

Modified dexamethasone suppression-corticotropin-releasing hormone stimulation test: A pilot study of young healthy volunteers and implications for alcoholism research in adolescents and young adults

The key neuroendocrine component of a response to stress is the hypothalamic-pituitary-adrenocortical (HPA) system. Abnormalities in the HPA system have been implicated in the pathophysiology of psychiatric disorders such as depression, post-traumatic stress disorder, alcoholism and suicide. The dexamethasone suppression test (DST) is the most frequently used test to assess HPA-system function in psychiatric disorders. This neuroendocrine test consists of the administration of a low dose of dexamethasone at 11 pm and the measurement of cortisol levels at one or more time points on the following day. After corticotropin-releasing hormone (CRH) became available for clinical studies, the DST was combined with CRH administration. In this test, patients are pretreated with a single dose of dexamethasone at 11 pm and receive human CRH intravenously at 3 pm the following day. The resulting DST-CRH test proved to be much more sensitive in detecting HPA system alterations than the DST. We have modified the DST-CRH test and used ovine CRH instead of human CRH in a pilot study of a group of young healthy volunteers. Results indicated that it produces results similar to the results obtained with human CRH. This suggests that ovine CRH can be used in psychiatric research. Alcoholism is associated with abnormalities in HPA function. Nonalcoholic subjects with a family history of alcoholism exhibit lower plasma ACTH and beta-endorphin as well as lower ACTH, cortisol, and beta-endorphin responses to psychological stress and CRH stimulation. This suggests that in children of alcoholics, alterations in the mechanisms that regulate HPA axis activity predate the development of alcohol dependence and may be considered inherited traits. Therefore, studies of the HPA system in persons at risk for alcoholism may help understand the neurobiological mechanisms of predisposition to alcoholism.

Central adiposity and cortisol responses to waking in middle-aged men and women.

Central obesity is associated with disturbances of hypothalamic-pituitary-adrenocortical (HPA) axis function. We investigated whether central adiposity indexed by waist/hip ratio is related to cortisol responses to waking and other measures of salivary cortisol over the working day. In total, 89 men and 83 women aged 47-59 y recruited from the British civil service. All were members of the Whitehall II epidemiological cohort. Saliva samples were collected on waking, 30 min later, and then at 2-h intervals from 0800-0830 to 2200-2230. A strict procedure for excluding individuals who did not adhere to the sampling schedule was applied. Waist/hip ratio in men was positively correlated with the cortisol response to waking (30 min-waking value) after adjusting for age, socioeconomic position, smoking status, alcohol consumption, time of waking, and cortisol level on waking (r=0.29, P=0.009). The cortisol response to waking was negatively related to high-density lipoprotein (HDL) cholesterol (r=-0.25) and positively with total/HDL cholesterol ratio (r=0.25). Associations between the decline in cortisol over the day and waist/hip ratio, HDL cholesterol and total/HDL cholesterol ratios were also significant. No associations were significant in women, and body mass index was unrelated to cortisol. The cortisol response to waking is a dynamic indicator of HPA function that has previously been related to chronic psychological stress. These results confirm a recent Swedish study, and indicate that cortisol responses to waking may be indicative of neuroendocrine disturbance in central obesity.

High neuroticism and depressive temperament are associated with dysfunctional regulation of the hypothalamic-pituitary-adrenocortical system in healthy volunteers.

Elevated neuroticism, depressive temperament and dysfunctional regulation of the hypothalamic-pituitary-adrenocortical (HPA) system are considered as risk factors for unipolar depression. An interaction of these vulnerability factors was suggested, but controversially discussed. In absence of other informative studies we set out for a replication test and for elucidation of the underlying mechanism. Ninety-two subjects recruited in the community-performed assessments of personality and temperament as well as measurement of HPA function with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Cortisol levels subsequent to Dex/CRH challenge were associated with neuroticism; high-neuroticism subjects revealed a higher HPA activation. This difference was mainly because of male subjects >/=25 years. A similar relationship was observed for depressive temperament. This constellation may propose that HPA dysregulation is the endocrinological basis for neuroticism and depressive temperament; this result supports the view that distinct personality factors and HPA vulnerability interact in mediating depression.

Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress.

Corticotropin-releasing hormone (CRH) is centrally involved in coordinating responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human affective disorders. To differentiate the CNS pathways involving CRH and CRH receptor 1 (Crhr1) that modulate behavior from those that regulate neuroendocrine function, we generated a conditional knockout mouse line (Crhr1(loxP/loxP)Camk2a-cre) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures, but not in the pituitary. This leaves the hypothalamic-pituitary-adrenocortical (HPA) system intact. Crhr1(loxP/loxP)Camk2a-cre mutants showed reduced anxiety, and the basal activity of their HPA system was normal. In contrast to Crhr1 null mutants, conditional mutants were hypersensitive to stress corticotropin and corticosterone levels remained significantly elevated after stress. Our data clearly show that limbic Crhr1 modulates anxiety-related behavior and that this effect is independent of HPA system function. Furthermore, we provide evidence for a new role of limbic Crhr1 in neuroendocrine adaptation to stress.

Altered hypothalamic–pituitary–adrenocortical function in rhesus monkeys ( Macaca mulatta) with self-injurious behavior

Individually housed rhesus monkeys sometimes spontaneously develop self-injurious behavior (SIB) in the form of self-directed biting that, on occasion, results in severe tissue damage and mutilation. We previously demonstrated lower levels of plasma cortisol in rhesus monkeys with a history of self-wounding (SW) when compared to non-wounders (NW). Furthermore, cortisol levels were negatively correlated with rates of self-directed biting. The present study was designed to further characterize the relationships between hypothalamic–pituitary–adrenocortical (HPA) activity, self-wounding, and self-directed biting. Basal 24-h urinary free cortisol excretion, the urinary free cortisol response to a low dose of dexamethasone, and the plasma cortisol response to ACTH were examined in 24 individually housed rhesus monkeys, based on wounding history, i.e. the presence/absence of a veterinary record of self-wounding, and current rates of self-directed biting, i.e. the median split of self-directed biting frequency (independent of wounding status). There were no reliable group differences on any of the physiological measures when analyzed by wounding history. However, the plasma cortisol response 30 min post-ACTH stimulation was significantly correlated with wounding recency, such that lower responsivity was associated with more recent wounding episodes. When the results were analyzed on the basis of biting frequency, high frequency biters (HFB) compared to low frequency biters (LFB) showed decreased HPA negative feedback sensitivity to dexamethasone and a trend towards an attenuated plasma cortisol response to ACTH stimulation. These findings suggest that SIB in socially reared monkeys is associated with complex changes in HPA axis function that are related to the expression of the pathology, i.e. self-directed biting, and to the recency of a wounding episode. It remains to be determined whether humans who exhibit SIB show similar alterations in HPA function.

Salivary cortisol patterns in vital exhaustion

Objective: The syndrome of vital exhaustion (VE), a risk indicator for myocardial infarction, is characterized by excessive fatigue, irritability, and demoralization. Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is a potential pathogenic mechanism in fatigue syndromes, but little is known about HPA function in syndromal VE. Method: We assessed basal free cortisol levels and responses to a speech task and to morning awakening by collecting multiple saliva samples over 2 days from 29 VE men and 30 controls. Results: VE subjects reported higher perceived stress, poorer sleep, and greater fatigue than controls. Basal cortisol levels were lower in VE subjects, especially in the evening, and were negatively associated with fatigue. Overall cortisol responses to the speech task were similar in VE and control groups, although VE subjects were less likely to show large (≥2.76 nmol/l) responses. The cortisol response to awakening was associated with concurrent fatigue and poor sleep quality. Conclusion: These findings suggest a subtle HPA hypoactivity in VE, which may arise through chronic stress and associated sleep disturbances.

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.

Long-lasting deficient dexamethasone suppression of hypothalamic-pituitary-adrenocortical activation following peripheral CRF challenge in socially defeated rats.

The present study focuses on the long-term changes in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis following two short-lasting episodes of intensive stress in the rat stress model of social defeat and the possible similarities with HPA functioning in human affective disorders. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long-term effect of these defeats on resting and ovine corticotropin-releasing factor (oCRF; intravenous (i.v.) 0. 5 microg/kg) induced levels of plasma ACTH and corticosterone (CORT) were measured 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CRF test (DEX; 25 microg/kg s.c., 90 min before oCRF injection, 0.5 microg/kg). The oCRF challenges were performed between 11.00 and 13.00 h (about three hours after start of the light phase). One week after defeat the ACTH response to CRF was significantly enhanced in defeated rats as compared to controls. Three weeks after defeat the ACTH response was back to control levels. The increased ACTH response 1 week after the stressor was not reflected in higher CORT levels. Neither were baseline ACTH and CORT levels affected by the prior stress exposure. DEX pretreatment inhibited pituitary adrenocortical activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was significantly higher in defeated rats as compared to controls both at one and three weeks after defeat. A reduced DEX suppression of baseline secretion of ACTH appeared 3 weeks after defeat. The same tendency was apparent in response and baseline values of CORT. The differences in CORT between socially stressed and control treated rats, however, did not reach significance. The possible role of changes in glucocorticoid-(GR) and mineralocorticoid receptor (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat GR-binding decreased in hippocampus and hypothalamus. No changes were observed in GR-binding in the pituitary nor in MR-binding in any of the regions analysed. Three weeks after defeat GR-binding recovered in hippocampus and hypothalamus but at this time MR-binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopressin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks after defeat and compared with controls. Social defeat failed to induce a change in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short-lasting stressors like defeat induce long-lasting, temporal dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.

Hormonal Response Pattern in the Combined DEX-CRH Test Is Stable over Time in Subjects at High Familial Risk for Affective Disorders

One of the major neurobiological alterations in depressive disorders consists in a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. This is reflected by a pathological increase in the adrenocorticotropin (ACTH) and cortisol release after pretreatment with 1.5 mg dexamethasone (DEX) the previous night and a challenge with 100 μg corticotropin-releasing hormone (CRH) the next day. The changes evoked by this combined DEX-CRH test recede partially with an improvement of the psychopathological symptoms of depressed patients. It is still unclear, however, whether this long-lasting disturbance of the HPA system is due to acquired changes in the acute illness or whether it plays a causal role and could be considered as a trait or vulnerability marker for depression. In a previous study we have examined the HPA function of healthy probands with a high genetic load for affective disorders. We found that this group of high-risk probands (HRPs) showed abnormal DEX-CRH test results with a cortisol release that was between that of a control group and a group of patients with depression. In a follow-up study we now reexamined 14 of the 47 HRPs about 4 years after the index investigation and found surprisingly constant DEX-CRH test results, so that one of the requirements for a vulnerability marker is fulfilled.

Hypothalamic-pituitary-adrenocortical activity and response to cognitive behavior therapy in unmedicated, hospitalized depressed patients

Surprisingly little research supports the hypothesis that depressions characterized by objective measures of neurobiological dysregulation respond poorly to psychotherapy. Moreover, relevant studies testing this hypothesis have been compromised by low rates of neurobiological abnormality in outpatient samples. The authors therefore investigated response to cognitive behavior therapy in relation to pretreatment measures of hypothalamic-pituitary-adrenocortical (HPA) activity in hospitalized, yet unmedicated, patients. The subjects were 29 unmedicated, hospitalized patients with major depression (DSM-III-R and Schedule for Affective Disorders and Schizophrenia/Research Diagnostic Criteria), nonpsychotic/nonbipolar subtype. After a 7- to 14-day evaluation, urinary free cortisol levels and dexamethasone suppression tests (DSTs) were obtained. Patients were treated for an average of 3 weeks with intensive individual cognitive behavior therapy. Response was assessed in relation to clinical severity of illness and pretreatment HPA parameters. Response to inpatient cognitive behavior therapy was inversely associated with pretreatment urinary free cortisol concentrations, although not strongly correlated with DST results. Overall, 12 (92%) of 13 cortisol suppressors on the DST who had normal urinary free cortisol concentrations responded to treatment, compared with only seven (44%) of the 16 patients characterized by nonsuppression of cortisol and/or elevated urinary free cortisol excretion. The relation between response to cognitive behavior therapy and HPA activity was not explained by clinical measures of symptom severity. Results are consistent with the hypothesis that patients with increased HPA function are less responsive to psychotherapy and, hence, might require somatic interventions. It is proposed that the negative impact of hypercortisolism on neurocognitive function mediates this relationship.