Elevated Basal Corticosterone Levels Research Articles

HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone's Psychomotor Effects in Female Mice.

Human immunodeficiency virus (HIV) is associated with neuroendocrine dysfunction which may contribute to co-morbid stress-sensitive disorders. The hypothalamic-pituitary-adrenal (HPA) or -gonadal (HPG) axes are perturbed in up to 50% of HIV patients. The mechanisms are not known, but we have found the HIV-1 trans-activator of transcription (Tat) protein to recapitulate the clinical phenotype in male mice. We hypothesized that HPA and/or HPG dysregulation contributes to Tat-mediated interactions with oxycodone, an opioid often prescribed to HIV patients, in females. Female mice that conditionally-expressed the Tat1–86 protein [Tat(+) mice] or their counterparts that did not [Tat(−) control mice] were exposed to forced swim stress (or not) and behaviorally-assessed for motor and anxiety-like behavior. Some mice had glucocorticoid receptors (GR) or corticotropin-releasing factor receptors (CRF-R) pharmacologically inhibited. Some mice were ovariectomized (OVX). As seen previously in males, Tat elevated basal corticosterone levels and potentiated oxycodone’s psychomotor activity in females. Unlike males, females did not demonstrate adrenal insufficiency and oxycodone potentiation was not regulated by GRs or CRF-Rs. Rather OVX attenuated Tat/oxycodone interactions. Either Tat or oxycodone increased anxiety-like behavior and their combination increased hypothalamic allopregnanolone. OVX increased basal hypothalamic allopregnanolone and obviated Tat or oxycodone-mediated fluctuations. Together, these data provide further evidence for Tat-mediated dysregulation of the HPA axis and reveal the importance of HPG axis regulation in females. HPA/HPG disruption may contribute vulnerability to affective and substance use disorders.

МЕЖСАМЦОВЫЕ ВЗАИМОДЕЙСТВИЯ НА НЕЙТРАЛЬНОЙ ТЕРРИТОРИИ И ПОСЛЕДУЮЩАЯ ДИНАМИКА УРОВНЯ КОРТИКОСТЕРОНА И ТЕСТОСТЕРОНА В КРОВИ У РУЧНЫХ И АГРЕССИВНЫХ СЕРЫХ КРЫС ( RATTUS NORVEGICUS )

Stress responses studied earlier in Norway rats (Rattus norvegicus) selected for the absence or enhancement of the aggressive–fearful attitude to humans (tame and aggressive behavior, respectively) were targeted mainly at nonsocial factors, whereas the data on the consequences of social stress induced, in particular, by interactions with a conspecific are scarce. It has already been shown that the selection of Norway rats for tame and aggressive behavior towards humans causes an attenuation or enhancement of intraspecific intermale aggression. In order to find out whether the differences in aggressiveness are accompanied by hormonal changes, variations of the blood levels of corticosterone and testosterone after the test for intermale aggression have been studied in tame, aggressive, and unselected rats reproduced in a vivarium for 7–8 generations as a reference. The goal of this work is to investigate the effect of selection for attitude to humans on agonistic interactions in an unfamiliar cage or in neutral territory and on the subsequent variation of blood corticosterone and testosterone levels in tame, aggressive, and unselected rats. In our experiments, tame males show longer attack latency than aggressive or unselected ones, and the duration of their aggressive behavior and the number of its patterns are much less, close to zero. In the test in neutral territory, aggressive rats are inferior to unselected in the overall time of confrontations. More pronounces signs of aggressiveness in unselected males in comparison to aggressive or tame are noted against the background of elevated basal corticosterone levels and elevated stress responsiveness. The lower aggressiveness of tame rats in the test in neutral territory correlates with the lower testosterone level after the test as compared to unselected or aggressive animals.

Elevated basal corticosterone levels increase disappearance risk of light but not heavy individuals in a long-term monitored rodent population

According to the cort-fitness hypothesis, glucocorticoid levels correlate negatively with fitness. However, field studies found mixed support for this hypothesis, potentially because the association between glucocorticoids and fitness might depend on prevailing environmental conditions. Based on the long-term monitoring of a natural rodent population, we tested whether individuals with elevated corticosterone levels were more likely to disappear, accounting for individual condition and among-year variation in food availability, population density and predation pressure. We used basal corticosterone levels measured at the onset of the pre-breeding season in 331 African striped mice from six generations. While basal corticosterone levels were highly repeatable within individuals, between-individual variation was large. Survival analysis revealed that disappearance risk over the pre-breeding season increased with elevated basal corticosterone levels for light but not for heavy individuals. High levels of corticosterone may be more deleterious to smaller individuals (i.e. through allostatic overload), eventually increasing their mortality risk, and disappearance would represent actual death. An alternative non-exclusive explanation could be that high levels of corticosterone selectively trigger dispersal in light individuals, and disappearance would rather reflect their departure from the population. Although environmental conditions varied considerably among generations, none of the interactions between corticosterone and environmental variables were significant. Disappearance probability was positively correlated with both predation pressure and with food availability, a factor favoring dispersal. In sum, elevated basal corticosterone levels increased disappearance in light striped mice, either directly via reduced survival prospects and/or indirectly via dispersal.

A human exposure based mixture of persistent organic pollutants affects the stress response in female mice and their offspring

Persistent organic pollutants (POPs) are found in the food chain of both humans and animals and exert a wide spectrum of potentially adverse effects. The present experiment aimed to investigate whether a defined mixture of 29 POPs, based on the dietary intake of Scandinavians, could affect the stress response in female mice exposed through ingestion, and in their offspring. Female mice 129:C57BL/6F0 hybrids were exposed from weaning, throughout pregnancy, and up until necropsy, to either 5000 × or 100 000 × the estimated daily intake for Scandinavians. The offspring were fed a reference diet containing no POPs. Both the mothers and their offspring were tested for basal and stress responsive corticosterone levels, and in an open field test to measure locomotor activity and anxiety-like behaviours. We found mothers to have elevated basal corticosterone levels, as well as a prolonged stress response following POP exposure. In the offspring, there was no effect of POPs on the stress response in females, but the exposed males had an over-sensitised stress response. There was no effect on behaviour in either the mothers or the offspring. In conclusion, we found a human relevant POP mixture can lead to subtle dysregulation of the hypothalamus-pituitary-adrenal axis in mice. As HPA axis dysregulation is commonly associated with neurological disorders, further studies should explore the relevance of this outcome for humans.

Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress

Major depression is hypothesized to be associated with dysregulations of the hypothalamic–pituitary–adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis.

Prenatal stress changes courtship vocalizations and bone mineral density in mice

Stress during the prenatal period has various effects on social and sexual behavior in both human and animal offspring. The present study examines the effects of chronic restraint stress in the second vs third trimester in pregnancy and glucocorticoid receptor (GR) heterozygous mutation on C57BL/6N male offspring’s vocal courtship behavior in adulthood by applying a novel analyzing method. Finally, corticosterone and testosterone levels as well as bone mineral density were measured.Prenatal stress in the third, but not in the second trimester caused a significant qualitative change in males’ courtship vocalizations, independent of their GR genotype. Bone mineral density was decreased also by prenatal stress exclusively in the third trimester in GR mutant and wildtype mice and – in contrast to corticosterone and testosterone – highly correlated with courtship vocalizations. In Gr+/− males corticosterone serum levels were significantly increased in animals that had experienced prenatal stress in the third trimester. Testosterone serum levels were overall increased in Gr+/− males in comparison to wildtypes as a tendency – whereas prenatal stress had no influence.Prenatal stress alters adult males’ courtship vocalizations exclusively when applied in the third trimester, with closely related changes in bone mineral density. Bone mineral density seems to reflect best the complex neuroendocrine mechanisms underlying the production of courtship vocalizations.Besides, we demonstrated for the first time elevated basal corticosterone levels in Gr+/− males after prenatal stress which suggests that the Gr+/− mouse model of depression might also serve as a model of prenatal stress in male offspring.

Sex differences in sleep, anhedonia, and HPA axis activity in a rat model of chronic social defeat

Repeated bouts of a major stressor such as social defeat are well known to induce a depression phenotype in male rats. Despite strong evidence and acknowledgement that women have a two-fold lifetime greater risk of developing major depression compared to men, the inclusion of female rats in studies employing social defeat are very rare; their absence is attributed to less aggressive interactions. This study sought to compare in male and female rats the impact of repeated social defeat, three times per week for four weeks, on the development of changes in sleep architecture and continuity, sucrose preference as a measure of anhedonia, changes in body weight, and basal plasma corticosterone levels. We found significant reductions in rapid eye movement sleep (REMS) during the light phase in both females and males, and significant increases in numbers of vigilance state transitions during the early dark phase in females but not in males. Additionally, females exhibited significantly greater reductions in sucrose intake than males. On the other hand, no sex differences in significantly elevated basal corticosterone levels were evident, and only the males exhibited changes in body weight. Taken together these findings suggest that the inclusion of female rats in studies of social defeat may offer greater insights in studies of stress and depression.

Does chronic stress enhance the risk of diseases?

In the everyday life, stress is deemed as something unfavorable that may enhance the risk for the development or worsen a disease. However, in its nature, stress is adaptive reaction of the body. Its main characteristic is the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Previously, we have shown that activation of the HPA axis plays a gastroprotective role during acute stress. The aim of our study was to clarify the effects of chronic stress and chronically elevated basal corticosterone levels on the gastric ulceration and cardiovascular vulnerability in rats. Male Wistar rats were repeatedly restrained 60 min daily for 14 days and examined on day 15th. The gastric ulceration was induced by a s.c. injection of indomethacin (35 mg/kg). The cardiovascular vulnerability was examined in urethane-anaesthetized rats in an experimental angina pectoris model (epinephrine, 10 µg/kg, 30 s later phentolamine, 15 mg/kg, both i.v.). We confirmed the development of chronic stress consequences by changes in several somatic parameters (body weight decrease, thymus involution, adrenal gland hypertrophy), and elevated resting corticosterone levels. However, the gastroprotective effect of chronic stress was not manifested and there was no aggravation of indomethacin-induced gastric ulceration, either. In the experimental angina pectoris model, previous chronic stress did not have any profound effect on the blood pressure, heart rate, and electrocardiogram changes. In contrast to the general view on the harmfulness nature of the stress, we were unable to find a harmful effect of chronic stress on the internal diseases (gastric ulceration and angina pectoris). However, its protective effect was also missing among present experimental conditions.

Stress, glucocorticoids and absences in a genetic epilepsy model

Although stress can alter the susceptibility of patients and animal models to convulsive epilepsy, little is known about the role of stress and glucocorticoid hormones in absence epilepsy. We measured the basal and acute stress-induced (foot-shocks: FS) concentrations of corticosterone in WAG/Rij rats, non-epileptic inbred ACI rats and outbred Wistar rats. The WAG/Rij strain is a genetic model for absence epilepsy and comorbidity for depression, which originates from the population of Wistar rats and, therefore, shares their genetic background. In a separate experiment, WAG/Rij rats were exposed to FS on three consecutive days. Electroencephalograms (EEGs) were recorded before and after FS, and the number of absence seizures (spike-wave-discharges, SWDs) was quantified.Both WAG/Rij rats and ACI rats exhibited elevated basal levels of corticosterone and a rapid corticosterone increase in response to acute stress. The WAG/Rij rats also displayed the most rapid normalization of corticosterone during the recovery phase compared to that of ACI and Wistar rats. FS had a biphasic effect on SWDs; an initial suppression was followed by an aggravation of the SWDs. By the third day, this aggravation of seizures was present in the hour preceding FS. This increase in SWDs may arise from anticipatory stress about the upcoming FS. Together, these results suggest that the distinct secretion profile of corticosterone found in WAG/Rij rats may contribute to the severity of the epileptic phenotype. Although the acute stressor results in an initial suppression of SWDs followed by an increase in SWDs, stress prior to a predictable negative event aggravates absences.

Impaired Hypothalamic Regulation of Endocrine Function and Delayed Counterregulatory Response to Hypoglycemia in Magel2-Null Mice

Hypothalamic dysfunction may underlie endocrine abnormalities in Prader-Willi syndrome (PWS), a genetic disorder that features GH deficiency, obesity, and infertility. One of the genes typically inactivated in PWS, MAGEL2, is highly expressed in the hypothalamus. Mice deficient for Magel2 are obese with increased fat mass and decreased lean mass and have blunted circadian rhythm. Here, we demonstrate that Magel2-null mice have abnormalities of hypothalamic endocrine axes that recapitulate phenotypes in PWS. Magel2-null mice had elevated basal corticosterone levels, and although male Magel2-null mice had an intact corticosterone response to restraint and to insulin-induced hypoglycemia, female Magel2-null mice failed to respond to hypoglycemia with increased corticosterone. After insulin-induced hypoglycemia, Magel2-null mice of both sexes became more profoundly hypoglycemic, and female mice were slower to recover euglycemia, suggesting an impaired hypothalamic counterregulatory response. GH insufficiency can produce abnormal body composition, such as that seen in PWS and in Magel2-null mice. Male Magel2-null mice had Igf-I levels similar to control littermates. Female Magel2-null mice had low Igf-I levels and reduced GH release in response to stimulation with ghrelin. Female Magel2-null mice did respond to GHRH, suggesting that their GH deficiency has a hypothalamic rather than pituitary origin. Female Magel2-null mice also had higher serum adiponectin than expected, considering their increased fat mass, and thyroid (T(4)) levels were low. Together, these findings strongly suggest that loss of MAGEL2 contributes to endocrine dysfunction of hypothalamic origin in individuals with PWS.

High susceptibility to chronic social stress is associated with a depression-like phenotype

Chronic stress is a key risk factor for a variety of diseases, including depression. There is a large degree of individual variation in the ability to recover successfully from a chronic stress exposure, but the determinants of this individual stress susceptibility are still poorly understood. We recently developed a novel mouse paradigm for chronic social stress during adolescence, which closely mimics the human condition of chronic social stress in respect to construct, face and predictive validity. By applying this chronic stress model to a large number of animals we aimed at identifying individuals that are either resilient or vulnerable to the persistent effects of chronic social stress exposure. Animals showing markedly elevated basal corticosterone levels 5 weeks following the end of the stress paradigm were considered "vulnerable", whereas individuals recovering quickly and being indistinguishable from controls were classified as "resilient". Stress vulnerability was associated with an increased level of corticotropin-releasing hormone in the paraventricular nucleus, decreased hippocampal mineralocorticoid receptor expression as well as increased anxiety- and depression-like behavior compared to resilient and control animals. In summary, we show that by using a large cohort of animals it is possible to select individuals that are vulnerable or resilient to the lasting effects of chronic social stress. The vulnerable phenotype mimics many aspects of stress-related human affective disorders and this may be used as a novel approach to study depression in an animal model, ultimately contributing to a better understanding and treatment of stress-related disorders.

The role of pituitary glucocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation following chronic social stress

One of the main physiological systems mediating adaptation to stressful stimuli is the hypothalamic-pituitary-adrenal (HPA) axis. Negative feedback control through glucocorticoids (GCs) is an important mechanism to restore homeostasis after HPA axis activation. GCs act via two receptor types, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). While MRs have been shown to regulate basal and circadian GC levels, GRs play a modulatory role in stressful situations, both acute and chronic. However, the contribution of different physiological subregions in negative feedback control is largely unknown. In this study we investigate the role of negative feedback via GCs on the level of the pituitary by utilizing pituitary-specific conditional GR knockout mice. Following 3 weeks of chronic social defeat, we observed an increase in anxiety-related behavior as well as elevated basal corticosterone levels in control mice. Mice with a GR deficiency in the pituitary show a diminished reaction to chronic stress as indicated by reduced corticosterone levels both basal and after acute stress. These findings are supported by behavioral data that showed decreased anxiety-like behaviour in knockouts compared to controls. In conclusion, we suggest that a lack of pituitary GRs results in a protective effect towards neuroendocrine and behavioral consequences of chronic stress. We hypothesize that this might be due to alterations in postnatal development of GR knockout mice.

Regulation of the hypothalamic-pituitary-adrenal axis in the neonatal rat: the role of maternal behavior.

There is a growing literature that indicates that exposure to elevated levels of glucocorticoids can result in long term consequences for the developing brain. In the developing rodent there is a period from about day 4-14 when the adrenal response to stress is either minimal or non-existent thus resulting in stable low levels of circulating glucocorticoids. This has been designated as the stress hypo-responsive period (SHRP). Numerous experiments have demonstrated that maternal factors are critical for the regulation of the pup's hypothalamic-pituitarty adrenal (HPA) axis and the maintenance of the SHRP. Following 24 h of maternal deprivation the neonatal rat shows elevated basal levels of corticosterone and exhibits a robust corticosterone and ACTH response to mild stress. Further c-fos mRNA in the paraventricular nucleus is enhanced following stress in deprived pups. At least three aspects of maternal behavior play a role in the regulation of the HPA axis during development. Tactile stimulation appears capable of inhibiting most of the brain-related changes that occur following maternal deprivation. Feeding is essential for maintaining the adrenal unresponsive and reduces the sensitivity of the adrenal to ACTH. Passive contact suppresses the response to stress. In the adult corticotropin-releasing hormone (CRH) is the major neuropeptide that controls pituitary ACTH secretion. In the maternally deprived pup CRH gene transcription is down regulated and arginine vasopressin (AVP) appears to assume the major regulatory hormone that modulates ACTH. These data all indicate that maternal factors are responsible for actively inhibiting the endocrine responses to stress postnatally. Further, maternal deprivation also results in increased cell death in several brain regions. Thus during development most of the peripheral and central stress responsive systems are capable of being activated. However, under conditions of normal dam-pup interactions these responses are mostly suppressed by the dam's behavioral interaction with the pups thus preventing the potential toxic effects of increased secretion of glucocorticoids during critical periods of brain development.

Primary social relationships influence the development of the hypothalamic–pituitary–adrenal axis in the rat

In the developing rodent, there is a period from about days 4 to 14 when the adrenal response to stress is either minimal or non-existent. This has been designated as the stress hyporesponsive period (SHRP). Numerous experiments have demonstrated that maternal factors are critical for the regulation of the pup's hypothalamic–pituitary–adrenal (HPA) axis and the maintenance of the SHRP. Following 24 h of maternal deprivation, the neonatal rat shows elevated basal levels of corticosterone (CORT) and exhibits a robust CORT and ACTH response to mild stress. Further, c- fos mRNA in the paraventricular nucleus (PVN) is enhanced following stress in deprived pups. At least three aspects of maternal behavior play a role in the regulation of the HPA axis during development. Tactile stimulation appears capable of inhibiting most of the brain-related changes that occur following maternal deprivation. Feeding is essential for maintaining the adrenal-unresponsive and reduces the sensitivity of the adrenal to ACTH. Passive contact suppresses the response to stress. In the adult, corticotropin-releasing hormone (CRH) is the major neuropeptide that controls pituitary ACTH secretion. In the maternally deprived pup, CRH gene transcription is downregulated and arginine vasopressin (AVP) appears to assume the major regulatory hormone that modulates ACTH. These data all indicate that maternal factors are responsible for actively inhibiting the endocrine responses to stress postnatally. Thus, during development, most of the peripheral and central stress-responsive systems are capable of being activated. However, under conditions of normal dam–pup interactions, these responses are mostly suppressed by the dam's behavioral interaction with the pups.

Long-term changes in mineralocorticoid and glucocorticoid receptor occupancy following exposure to an acute stressor

Stressors produce rapid activation of the hypothalamic–pituitary–adrenal axis, which typically resolves within 60–90 min following termination of the stressor. In addition, some stressors such as inescapable tailshock (IS) also produce elevated basal levels of corticosterone (CORT), and reduced serum levels of corticosteroid binding globulin (CBG). The elevated basal levels of CORT produced by IS are only observed at the trough of the circadian rhythm of CORT secretion, and are sustained for 2–3 days following stressor termination. The goal of the following experiments was to determine the extent to which the elevated basal levels of CORT observed following IS exposure produced greater corticosteroid receptor occupancy in the brain and pituitary. To do so, rats ( n=8–10 per group) received either sham or bilateral adrenalectomy (with CORT replacement in their drinking water; 25 μg/ml) and were given 3 days to recover. Rats were then exposed to 100 ISs (1.6 mA, 5 s each) administered on a 60 s variable intertrial interval, or remained in their home cages. As seen previously, IS produced an increase in basal CORT (5 μg/dl) and a decrease in CBG (30% decrease). Rats were sacrificed 24 h following IS for trunk blood samples and brain dissections. IS exposure had very little effect on corticosteroid receptor protein expression as determined by mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) binding levels in ADX rats. In addition, no changes in whole cell GR levels (as detected by Western blot) were observed in sham rats exposed to IS. On the other hand, IS exposure led to greater occupancy of MR (ranging from 25%–50%) in hippocampus, hypothalamus, pituitary, and posterior cortex. IS also produced greater occupancy of GR (approximately 20%) in hypothalamus and posterior cortex. These long-term changes in corticosteroid receptor activation, evident 24 h after IS exposure, may be responsible for some of the long-term neural, behavioral and immune changes observed following this acute stress procedure.

Neurotoxic Lesions Induced by Monosodium Glutamate Result in Increased Adenopituitary Proopiomelanocortin Gene Expression and Decreased Corticosterone Clearance in Rats

Hypothalamic-pituitary-adrenocortical function in rats with brain lesions induced by neonatal monosodium glutamate (MSG) treatment (4 mg/g, 5 administrations, i.p.) was evaluated in the present study. Using in situ hybridization we found increased proopiomelanocortin (POMC) mRNA levels in the adenopituitary and normal corticotropin-releasing hormone mRNA levels in the hypothalamic paraventricular nucleus in MSG-treated rats. The total content of pituitary adrenocorticotropin (ACTH) was not changed, while pituitary ACTH concentration was higher in MSG-treated compared to control rats. The number of ACTH-immunostained cells per a constant area of adenohypophysial section, as measured by immunohistochemistry, was unchanged indicating that no significant condensation of corticotropes occurred. Basal plasma ACTH concentrations were not different, whereas morning corticosterone levels were elevated in rats with MSG treatment. While ACTH response to stress stimuli was similar in both groups of rats, corticosterone response to exogenous ACTH (500 ng/kg, i.v., Synacthen), short-lasting handling and immobilization was of the same magnitude but prolonged in MSG-treated rats. Based on the decline of [³H]corticosterone in plasma, a decreased corticosterone clearance rate was found in MSG-treated rats. These findings suggest that MSG treatment results in increased POMC gene expression per corticotrope of the atrophic pituitary resulting in maintenance of normal pituitary ACTH stores and plasma ACTH levels. Elevated basal levels of corticosterone in plasma as well as prolonged corticosterone responses to stimulations in rats treated with MSG seem to be due to a decreased clearance rate of corticosterone.

Evidence for mineralocorticoid receptor facilitation of glucocorticoid receptor-dependent regulation of hypothalamic-pituitary-adrenal axis activity.

These studies further evaluated the relative role of mineralocorticoid (type I) and glucocorticoid (type II) receptors in mediating corticosteroid feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Acute treatment of rats with the selective mineralocorticoid receptor antagonist, RU28318 (50 mg/kg sc), produced elevated basal corticosterone levels in the morning, but had no effect on basal corticosterone levels in the evening or on restraint stress corticosterone levels at either time of day. Acute treatment with the selective glucocorticoid receptor antagonist, RU40555 (30 mg/kg sc) had no effect on basal or restraint stress corticosterone levels at either time of day. However, combined treatment with RU28318 and RU40555 produced an elevation of evening basal corticosterone levels (and morning basal on one occasion) and produced an increase in corticosterone levels during and after stress at both times of day. In a separate experiment conducted in the morning, the combined RU28318 and RU40555 treatment also produced elevated ACTH responses during restraint stress. Based on available corticosteroid receptor measures, the RU28318 treatment was estimated to selectively occupy approximately 85% of mineralocorticoid receptors in rat brain, whereas the RU40555 treatment was estimated to selectively occupy approximately 50% of glucocorticoid receptors in rat brain. We conclude that mineralocorticoid receptor activation is necessary and sufficient to maintain low basal corticosterone levels during the circadian trough, whereas glucocorticoid receptor activation is necessary to constrain corticosterone secretion during the circadian peak or during acute stress. However, even during the circadian peak or acute stress, mineralocorticoid receptor activation plays an important role in facilitating the glucocorticoid receptor dependent regulation of HPA axis activity by corticosterone.

Conditioned neuroendocrine and cardiovascular stress responsiveness accompanying behavioral passivity and activity in aged and in young rats

Mean arterial pressure (MAP), heart rate (HR), plasma epinephrine (E), plasma norepinephrine (NE), and plasma corticosterone (CORT) were measured in 3-month- and 24-month-old male Wistar rats exposed to a conditioned emotional stress response (CER) paradigm and a conditioned defensive burying (CDB) paradigm. In the CER situation blood samples were taken during reexposure to the training environment one day after a single inescapable footshock (0.6 mA, AC for 3 s) had been administered. In the CER paradigm the young rats displayed passive behavior (immobility) accompanied by an increase in plasma levels of CORT and E, whereas both the control and conditioned animals showed increased NE responses. Previously shocked aged rats exhibited an attenuated plasma NE response, whereas levels of E remained elevated to a greater extent. Aged animals showed elevated basal levels of CORT one day after footshock administration. Stress-induced immobility was preserved in the aged rats. These animals had an increase in basal MAP values and a decrease in basal HR values compared to young ones. In the CDB paradigm, rats were exposed to a nonelectrified probe 1 day after the repeated shock (2 mA/contact) procedure. Young rats displayed defensive burying accompanied by increments in MAP, HR, CORT, and NE. The aged animals showed similar hormonal, autonomic, and behavioral stress responses. Thus, the age-related alterations in neuroendocrine and autonomic response patterns are apparent in stressed animals during behavioral passivity in absence of control (CER) rather than during active control (defensive burying).

Perinatal malnutrition and early handling: interactive effects on the development of the pituitary-adrenal system.

The preweaning development of the pituitary-adrenal system was investigated in perinatally malnourished rodents. Malnourished pups that were routinely handled displayed an earlier plasma corticosterone stress response to electric shock and an accelerated development of feedback inhibition of the stress response by exogenously elevated steroid levels. Although malnourished pups displayed elevated basal corticosterone levels compared to well-fed controls, the post-stress levels were also higher in these malnourished young. Thus, the corticosterone response to stress was not impaired in malnourished pups. The influence of the early handling of malnourished young on pituitary-adrenal activity was also studied. Whereas the accelerated development of the stress response and the elevated post-shock levels were not the result of early handling, the elevated basal corticosterone levels displayed by handled malnourished pups were not present in nonhandled malnourished pups. Thus, the early non-nutritional environment interacts with malnutrition to alter the development of the pituitary-adrenal system.