Higher Corticosterone Concentrations Research Articles

Corticosterone is not correlated with nest departure in snowy owl chicks ( Nyctea scandiaca)

Snowy owl chicks typically depart from nests at approximately 18 days of age, but 3 weeks before taking their first flight. High concentrations of corticosterone have been implicated in behavioral changes in many species, leading us to assess corticosterone’s role in chick nest departure. Corticosterone titers in free-living chicks, however, do not predict this departure event. Baseline corticosterone concentrations decrease as chicks age. By 13 days, corticosterone concentrations are 50% of concentrations in 1-day-old chicks. Baseline concentrations, however, do not differ between departed and nest-bound chicks. Furthermore, corticosterone concentrations become significantly elevated 30 min after collecting the baseline sample, indicating that chicks are able to mount a corticosterone response to handling. This stress-induced rise in corticosterone also did not differ between departed and nest-bound chicks. Brood sizes varied, possibly resulting in increased stress in chicks from larger broods. Although many chicks died before reaching departure age, brood sizes at time of nest departure ranged from 1 to 10 chicks. Brood size was not correlated with age of nest departure or individual corticosterone concentrations. These data indicate that it is unlikely that corticosterone plays a role in triggering nest departure in snowy owl chicks.

Serum 17-α-hydroxyprogesterone and corticosterone concentrations in dogs with nonadrenal neoplasia and dogs with suspected hyperadrenocorticism

To assess serum 17-alpha-hydroxyprogesterone (17OHP) and corticosterone concentrations in dogs with nonadrenal neoplasia and dogs being screened for hyperadrenocorticism. Prospective study. 16 clinically normal dogs, 35 dogs with nonadrenal neoplasia, and 127 dogs with suspected hyperadrenocorticism. ACTH stimulation tests were performed in all dogs. Baseline serum cortisol and corticosterone concentrations were measured in the healthy dogs; baseline serum cortisol concentration and ACTH-stimulated cortisol, corticosterone, and 17OHP concentrations were measured in all dogs. Endogenous plasma ACTH concentration was also measured before administration of ACTH in dogs with neoplasia. In 35 dogs with neoplasia, 31.4% had high serum 17OHP concentration and 22.9% had high serum corticosterone concentration. Of the 127 dogs with suspected hyperadrenocorticism, 59 (46.5%) had high ACTH-stimulated cortisol concentrations; of those, 42 of 59 (71.2%) and 32 of 53 (60.4%) had high serum 17OHP and corticosterone concentrations, respectively. Of dogs with serum cortisol concentration within reference range after ACTH administration, 9 of 68 (13.2%) and 7 of 67 (10.4%) had high serum 17OHP and corticosterone concentrations, respectively. In the dogs with neoplasia and dogs suspected of having hyperadrenocorticism, post-ACTH serum hormone concentrations were significantly correlated. Serum concentrations of 17OHP or corticosterone after administration of ACTH may be high in dogs with nonadrenal neoplasia and no evidence of hyperadrenocorticism. Changes in serum 17OHP or corticosterone concentrations after administration of ACTH are proportionate with changes in cortisol concentration.

Japanese Quail Selected for High Plasma Corticosterone Response Deposit High Levels of Corticosterone in Their Eggs

Poor habitat quality or body condition often correlates with high responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis rather than with elevated baseline levels of glucocorticoids. We hypothesized that, for egg-laying vertebrates, high responsiveness of the HPA axis would correspond to high concentrations of corticosterone in yolk. We tested the prediction that Japanese quail (Coturnix coturnix japonica) selected for high plasma corticosterone response to brief immobilization (HS quail) would lay eggs with higher yolk corticosterone concentrations than birds selected for low response (LS quail). Quail from both lines were left undisturbed, outside of the stressors associated with daily management, before a first round of egg collection. In a second experiment, quail of both lines were experimentally stressed during the week before egg collection. In both cases we found quail from the HS line to lay eggs with significantly higher yolk corticosterone concentrations than quail of the LS line. After exposure to added experimental stressors, the line difference was more pronounced (increasing from 62% to 96%). There was no line difference in concentrations of yolk testosterone. Our results suggest that (1) genetic differences underly differences in the transfer of maternal corticosterone to yolk and (2) females may be able to control deposition of corticosterone into yolk through a mechanism independent of baseline corticosterone titers.

Stress hormone and male reproductive function

The Leydig cell is the primary source of testosterone in males. Levels of testosterone in circulation are determined by the steroidogenic capacities of individual Leydig cells and the total numbers of Leydig cells per testis. Stress-induced increases in serum glucocorticoid concentrations inhibit testosterone-biosynthetic enzyme activity, leading to decreased rates of testosterone secretion. It is unclear, however, whether the excessive glucocorticoid stimulation also affects total Leydig cell numbers through induction of apoptosis and thereby contributes to the stress-induced suppression of androgen levels. Exposure of Leydig cells to high concentrations of corticosterone (CORT, the endogenously secreted glucocorticoid in rodents) increases their frequency of apoptosis. Studies of immobilization stress indicate that stress-induced increases in CORT are directly responsible for Leydig cell apoptosis. Access to glucocorticoid receptors in Leydig cells is modulated by oxidative inactivation of glucocorticoid by 11 beta-hydroxysteroid dehydrogenase (11 betaHSD). Under basal levels of glucocorticoid, sufficient levels of glucocorticoid metabolism occur and there is likely to be minimal binding of the glucocorticoid receptor. We have established that Leydig cells express type 1 11 betaHSD, an oxidoreductase, and type 2, a unidirectional oxidase. Generation of redox potential through synthesis of the enzyme cofactor NADPH, a byproduct of glucocorticoid metabolism by 11 betaHSD-1, may potentiate testosterone biosynthesis, as NADPH is the cofactor used by steroidogenic enzymes such as type 3 17beta-hydroxysteroid dehydrogenase. In this scenario, inhibition of steroidogenesis will only occur under stressful conditions when high input amounts of CORT exceed the capacity of oxidative inaction by 11 betaHSD. Changes in autonomic catecholaminergic activity may contribute to suppressed Leydig cell function during stress, and may explain the rapid onset of inhibition. However, recent analysis of glucocorticoid action in Leydig cells indicates the presence of a fast, non-genomic pathway that will merit further investigation.

Increased Stress Reactivity as a Possible Factor of Early Degenerative Changes in OXYS Rats

After stress (immobilization in cages) plasma corticosterone level in prematurely aging OXYS rats was higher, while the content of NO metabolites was much lower than in Wistar rats. Stress increased blood pressure in OXYS and Wistar rats, the maximum values were observed in control and stressed OXYS rats. The concentration of reduced glutathione in the brain of OXYS rats was lower than in Wistar rats. After immobilization the concentration of reduced glutathione decreased in animals of both strains. The concentration of oxidized protein increased by 1.5 times only in OXYS rats. SOD activity remained unchanged, but in OXYS rats this parameter was higher than in Wistar rats. It can be hypothesized that high blood pressure, low NO content, high corticosterone concentration, and stress-induced deficiency of the antioxidant system (or combined effects of these factors) contribute to the development of neurodegenerative changes in the brain of OXYS rats.

Choline exposure reduces potentiation of N-methyl- d-aspartate toxicity by corticosterone in the developing hippocampus

Exposure to high levels of glucocorticoids (GCs) may adversely affect neuronal viability, particularly in the developing hippocampus, via increased function or sensitivity of N-methyl- d-aspartate (NMDA)-type glutamate receptors. Conversely, choline supplementation in the developing brain may reduce the severity of subsequent insult. The present studies aimed to examine the extent to which short-term exposure to high concentrations of corticosterone would produce neuronal injury mediated by NMDA receptor activity. These studies also assessed the ability of choline to prevent this form of injury via interactions with nicotinic acetylcholine receptors (nAChRs) expressing the α7 subunit. Organotypic hippocampal slice cultures derived from neonatal rat were pre-treated for 72 h with corticosterone (100 nM) alone or with choline (0.1–10 mM), prior to a brief (1 h) NMDA exposure (5 μM). NMDA exposure produced significant cellular damage, reflected as increased fluorescence of the non-vital marker propidium iodide, in the CA1 region. While exposure to corticosterone alone did not produce damage, pre-treatment of cultures with corticosterone markedly exacerbated NMDA-induced toxicity. Pre-treatment with choline (≥1 mM) alone or in combination with corticosterone markedly reduced subsequent NMDA toxicity, effects blocked by co-exposure to methyllycaconitine (100 nM), an antagonist active at nAChRs expressing the α7 subunit. These data suggest that even short-term exposure to high concentrations of GCs may adversely affect neuronal viability and that choline supplementation protects the brain from NMDA receptor-mediated damage, including that associated with hypercortisolemia.

The cytoprotective effect of inulin-type hexasaccharide extracted from Morinda officinalis on PC12 cells against the lesion induced by corticosterone

High concentration of corticosterone (Cort) 0.2 mM was incubated with PC12 cells to simulate the lesion state of brain neurons in depressive illness, it was found that the inulin-type oligosaccharides extracted from Morinda officinalis, inulin-type hexasaccharide (IHS) at the doses of 0.625, 1.25 μM or desipramine (DIM) 0.25, 1 μM protected the PC12 cells from the lesion induced by Cort. With Fura-2/AM labeling assay, DIM 0.25, 1 μM or IHS 2.5, 10 μM attenuated the intracellular Ca 2+overloading induced by Cort 0.1 mM for 48 h in PC12 cells. Using RT-PCR, treatment with Cort 0.1 mM for 48 h decreased the nerve growth factor (NGF) mRNA level in PC12 cells, IHS 5, 10 μM reversed this change. In summary, IHS attenuate the intracellular Ca 2+overloading and thereby up-regulate the NGF mRNA expression in Cort-treated PC12 cells, which may be consisted at least part of the cytopretective effect of IHS. These results also extend evidence for our hypothesis that neuroprotective action is one of the common mechanisms for antidepressants.

Impact of chronic catheterization and automated blood sampling (Accusampler) on serum corticosterone and fecal immunoreactive corticosterone metabolites and immunoglobulin A in male rats

Jugular catheters were inserted in nine male rats under general isofluorane anesthesia and the catheters were connected to a commercially available computerized blood sampling device (Accusampler). Blood samples (150 microl) were collected every 4 h during the first 24 h after surgery and every 12 h during the following 72 h until 94 h after surgery, when the animals were killed. All fecal pellets were collected at blood sampling. Serum corticosterone and fecal concentrations of immunoreactive corticosterone metabolites and immunoglobulin A (IgA) were quantified by ELISAs. In blood, high corticosterone concentrations (>200 ng/ml) were recorded in the first samples obtained after surgery, but the concentrations decreased steadily during the day and became cyclical, showing a diurnal variation with high levels during evenings and low levels in the mornings. The automatic blood sampling itself did not result in recordable increases in serum corticosterone concentrations. The time delay between the presence of elevated corticosterone levels in blood and in feces was approximately 12 h. Fecal immunoreactive corticosterone metabolite levels remained elevated during the 94 h study period after surgery. The fecal concentrations of IgA showed substantial between-animal variation and decreased non-significantly after the surgery. Like serum corticosterone, fecal IgA showed a diurnal variation in amounts excreted, in this case with high values in the morning and low values in the evening. The concentrations of fecal corticosterone and IgA were negatively correlated in samples obtained before surgery but no correlation existed after surgery. This indicates that fecal immunoreactive corticosterone metabolites, but not IgA, constitute a good marker of acute stress. For immunoreactive corticosterone metabolites as well as for IgA, the concentration in feces correlated well with total excretion, making single fecal samplings usable as a measure of total secretion.

Chronic ethanol administration and withdrawal decreases 5-HT1A mRNA, but not 5-HT4 expression in the rat hippocampus.

Chronic ethanol administration and withdrawal decreases 5-HT1A mRNA, but not 5-HT4 expression in the rat hippocampus.

The effect of melatonin and corticosterone on the phagocytic function of BALB/c mice macrophages

The hormones melatonin and corticosterone are able to modulate the immune response, with indications that melatonin may counteract the immunosuppressory action of the glucocorticoids. The aim of the present study is to evaluate the effects of pharmacological concentrations of melatonin and corticosterone, singly and together, on macrophage phagocytosis of antigen particles. To this end we performed an in vitro study using as phagocytes peritoneal macrophages from two groups of BALB/c mice, one in a basal situation and the other subjected to stress by swimming. The concentrations used were ten and one hundred times greater than the previously determined physiological levels. In particular, for incubations with macrophages from the basal group they were 0.9 pg/ml and 9 pg/ml of melatonin, and 2 μ g/ml and 20 μ g/ml of corticosterone, and for macrophages from the stressed group they were 0.7 pg/ml and 7 pg/ml of melatonin, and 5 μ g/ml or 50 μ g/ml of corticosterone. The results indicate that the immunomodulatory effect of the two hormones depends on the conditions of the study. Thus, melatonin led to increased phagocytic capacity in macrophages from both the basal and the stressed animals, while corticosterone only had an immunostimulatory effect with macrophages from the unstressed animals. With both hormones acting together, the macrophage phagocytic activity was stimulated at all the concentrations used and independently of whether or not the corresponding animals had been stressed, although the greatest activation was seen in the basal animal phagocytes incubated with the higher corticosterone concentration. In conclusion, while melatonin was definitely immunostimulatory at the concentrations tested, the immunoregulatory properties of corticosterone depended on the situation.

Duration of transcranial magnetic stimulation effects on the neuroendocrine stress response and coping behavior of adult male rats

Background: Transcranial magnetic stimulation (TMS) is a relatively novel, noninvasive method of altering cerebral electrophysiological activity that produces localized and reversible changes in brain tissue. TMS has been shown to have antidepressant properties in both human trials and animal models. Additionally, TMS may alter hypothalamic–pituitary–adrenal (HPA) function resulting in a normalized dexamethasone suppression test in some depressed subjects and an attenuated stress-induced increase in adrenocorticotropic hormone (ACTH) and a possibly lowered basal corticosterone (CORT) concentration in rats. This research was undertaken to investigate the duration of these behavioral and neuroendocrine effects of TMS in rats. Methods: In this study, serum ACTH, CORT, testosterone, and luteinizing hormone (LH) concentrations following and immobility parameters during a forced-swim test in adult male rats were evaluated immediately and 1, 3, 5, 7, and 14 days subsequent to a 10-day course of once-daily TMS or sham application. Results: TMS animals had significantly higher ACTH and CORT concentrations immediately following the 10-day course of TMS compared to sham controls. Higher CORT concentrations (numerically but not statistically) were displayed by TMS-treated animals 1 and 3 days after the 10-day application course, although there were no significant differences between TMS and sham groups for ACTH or CORT levels 1, 3, 5, 7, and 14 days following application of sham or TMS. No significant differences were found between groups for serum testosterone and LH levels at any given collection time point. Immobility time, a measure of coping ability that is predictive of human antidepressant response, was significantly decreased (i.e., time spent actively swimming was significantly increased) immediately after the 10-day course of TMS. Thereafter, a nonsignificant numerical trend at 1 and 3 days after TMS application for immobility times between the TMS and control groups was observed (TMS<control values). No significant differences in immobility between TMS and control animals were found at subsequent time points. Conclusions: The present findings suggest that the HPA stress axis is significantly altered immediately following a 10-day course of TMS in that a significant increase in ACTH and CORT levels in TMS-treated animals corresponded to a significant decrease in immobility times in the forced-swim test compared to control values. Finally, based upon the obtained results, the TMS effects in rats appear to be of relatively short duration.

Genetic selection for coping style predicts stressor susceptibility.

Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls. The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behaviour in the forced swimming test than LAL controls. Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyse the role of genetic factors in the individual differences in stress-related psychopathology.

Hyper- or hypothyroidism: its association with the development of ascites syndrome in fast-growing chickens

The ascites syndrome in broiler chickens is attributed to the progress in genetic selection for rapid growth, coupled with the metabolic burden imposed by exposure to a relatively low-ambient temperature ( T a). The syndrome is mainly characterized by hematocrit elevation, decline in blood oxygen saturation, accumulation of fluid in the abdominal cavity, and finally, death. Ascitic chickens have demonstrated hypothyroidism coupled with a marked stress response (high corticosterone concentration) and reduction in the hemoglobin content. The objective of the present study was to examine the role of thyroid and corticosterone hormones in the development of the syndrome. Ascites was induced by exposure to a gradually declining T a and supplementation of a pellet-form diet. Exogenous thyroxin (T 4) and propylthiouracil (PTU) (in Experiments 1 and 2, respectively) were supplemented in drinking water to induce hyper- or hypothyroidism, respectively. Ascites syndrome was developed in 21.5% and 23% of the birds exposed to ascites-induced conditions (Exps. 1 and 2, respectively). Excess T 4 (Exp. 1) significantly reduced the percentage of ascites (down to 7%), whereas PTU (Exp. 2) significantly increased the appearance of the syndrome (35%). In the T 4-treated chickens, although the T 4 concentration reached pharmacological levels, the triiodothyronine (T 3) concentration remained within physiological levels, whereas T 3 in the ascitic birds exhibited a reduction pattern similar to that observed in the ascitic non-supplemented ones. In the PTU-treated chickens, however, both ascitic and non-ascitic birds demonstrated significant reductions in both T 4 and T 3 concentrations. In both experiments, ascitic chickens exhibited a considerable stress response, characterized by a significant and persisted elevation in plasma corticosterone concentration, which was in accordance with a similar elevation of hematocrit, and the PTU-treated non-ascitic birds exhibited a similar stress response. At 5 weeks of age, ascitic birds and the PTU-treated non-ascitic ones exhibited significant reductions in the hemoglobin content of their red blood cells. It may be concluded that deficiency in the thyroid hormones and elevated corticosterone may play a key deleterious role in the development of the ascites syndrome.

Baseline and stress-induced levels of corticosterone during different life cycle substages in a shorebird on the high arctic breeding grounds.

After a migratory flight of several thousand kilometers to their high arctic breeding grounds, red knots (Calidris canutus islandica, Scolopacidae) showed high baseline concentrations of plasma corticosterone (58 ng/mL). Such high baseline corticosterone levels may be conditional for the right behavioral and metabolic adjustments to environmental and social stresses that shorebirds experience on arrival in an unpredictable tundra breeding environment. Despite the high baseline levels of corticosterone, red knots still showed a marked stress response during the postarrival period, with corticosterone concentrations increasing significantly during a 60-min period of confinement. Baseline levels of corticosterone declined as the breeding season progressed. Red knots with brood patches, that is, birds that had completed egg laying and commenced incubation, had a reduced adrenocortical response to the stress of confinement compared with red knots with no, or with half-developed, brood patches. This is consistent with the idea that birds breeding in extreme environments with short breeding seasons may exhibit a decreased adrenocortical response to stressful events to prevent high corticosterone concentrations from inducing interruptions of reproductive behavior.

Centrally regulated blood pressure response to vasoactive peptides is modulated by corticosterone.

To investigate the role of brain glucocorticoid (GR) and mineralocorticoid receptors (MR) in centrally evoked blood pressure responses, the effects of intracerebroventricular (i.c.v.) administration of angiotensin II and vasopressin were studied in adrenalectomized rats with and without corticosterone or aldosterone replacement. Five groups were examined: (i) Adrenalectomy (ADX); (ii) ADX + a subcutaneously implanted 20-mg corticosterone pellet (low corticosterone); (iii) ADX + 100 mg corticosterone pellet (high corticosterone); (iv) ADX + 6 microg/24 h aldosterone via Alzet minipump (Aldo); and (v) Sham adrenalectomy (Sham). Pressor responses to 150 ng angiotensin II and 50 ng vasopressin i.c.v. were determined in freely moving rats using biotelemetry. The results show that, compared to sham rats, ADX rats showed significantly reduced pressor responses. This reduction of the pressor response to angiotensin II could be reversed and even further enhanced by replacement of the ADX rats with high corticosterone concentrations. In contrast, with aldosterone, a depressor type response was observed. Corticosterone replacement could not restore the pressor response to vasopressin. We conclude that the pressor response to centrally administered vasoactive substances is substantially attenuated by removal of the adrenals and that, in the case of angiotensin II, this is due to the lack of high concentrations of circulating corticosterone occupying both MR and GR. However, predominant MR occupancy appears to play an opposite role and attenuates the angiotensin II-induced pressor response.

MRNA and enzyme activity of hepatic 11β-hydroxysteroid dehydrogenase type 1 are elevated in C57BL/KsJ-db/db mice

To evaluate the importance of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in insulin resistant diabetic C57BL/KsJ-db/db mice, we measured the activity and mRNA level of 11β-HSD1 in the liver of db/db mice and their heterozygote litter mates, db/+m mice. The blood glucose, plasma insulin, and corticosterone levels of db/db mice were significantly higher than those of db/+m mice. Despite hyperinsulinemia, the activity level of this enzyme was significantly higher in db/db mice, and the mRNA level of hepatic 11β-HSD1 was also significantly higher in db/db mice. Since hepatic 11β-HSD1 in vivo mainly functions as 11-keto-reductase and does not work as 11β-oxidase, these results suggest that the rate of hepatic conversion of 11-dehydrocorticosterone to corticosterone is increased in db/db mice, resulting in higher glucocorticoid activity in the liver. The increased hepatic corticosterone concentration due to the elevation of 11β-HSD1 and high plasma corticosterone concentration may antagonize the action of insulin and cause insulin resistance. These findings have a potentially important implication for relationships between increased hepatic 11β-HSD1 and insulin resistance in db/db mice. The present paper is the first to demonstrate the increased activities and mRNA level of hepatic 11β-HSD1 in db/db mice.

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression.

The relationship between stressful life events and the onset of disease is well documented. However, the role of psychological stress as a risk factor for life-threatening cerebrovascular insults such as stroke remains unspecified, but could explain individual variation in stroke outcome. To discover the mechanisms through which psychological stress may alter stroke outcome, we modeled the effects of chronic social intimidation and stress on ischemia-induced bcl-2 expression and early neuronal cell loss resulting from cerebral artery occlusion in mice (C57BL/6). The bcl-2 protooncogene promotes cell survival and protects against apoptosis and cellular necrosis in numerous neurodegenerative disorders, including stroke. In our study, male mice were chronically exposed to aggressive social stimuli before induction of a controlled, mild ischemic insult. Stressed mice expressed approximately 70% less bcl-2 mRNA than unstressed mice after ischemia. In addition, social stress greatly exacerbated infarct in wild-type mice but not in transgenic mice that constitutively express increased neuronal bcl-2. Despite similar postischemic concentrations of corticosterone, the major stress hormone in mice, high corticosterone concentrations were significantly correlated with larger infarcts in wild-type mice but not bcl-2 transgenic mice. Thus, enhanced bcl-2 expression offsets the potentially deleterious consequences of high postischemic plasma corticosterone concentrations. Taken together, these data demonstrate that stressful prestroke social milieu strongly compromises an endogenous molecular mechanism of neuroprotection in injured brain and offer a new behavioral target for stroke therapy.

Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots.

Chronic stress stimulates corticosterone secretion and recruits brain pathways that regulate energy balance (caloric acquisition and deposition) and facilitate hypothalamic-pituitary-adrenal responsiveness to new stressors. We implanted corticosterone or cholesterol bilaterally either near the central nucleus of the amygdala (CeA) or in the prefrontal cortex to determine whether high concentrations of the steroid act at either site, with or without chronic stress. Rats were adrenalectomized and treated systemically with low doses of corticosterone. Half were maintained at room temperature and the other half were exposed to 5 degrees C cold for 5 days before all rats were restrained. There was limited diffusion of corticosterone from brain implants. Corticosterone in prefrontal cortex, but not CeA, decreased plasma insulin and adrenocorticotropic hormone (ACTH) responses to acute restraint in both control and chronically cold stressed rats. Corticosterone implants near CeA decreased the weight of fat depots only in cold; corticosterone implants in prefrontal cortex were ineffective. We conclude that (i) corticosterone inhibits insulin and ACTH secretion by an action in prefrontal cortex but not CeA; (ii) high concentrations of corticosterone secreted during chronic stress alter metabolism through (autonomic) outputs of the CeA and prefrontal cortex in site- and variable-specific fashion; and (iii) the amygdala is a component of a stress-recruited, state-dependent pathway.

Neurobiological Correlates of Individual Differences in Novelty-Seeking Behavior in the Rat: Differential Expression of Stress-Related Molecules

It is well established that individual rats exhibit marked differences in behavioral responses to a novel environment. Rats that exhibit high rates of locomotor activity and sustained exploration in such an environment also exhibit high concentrations of stress-induced plasma corticosterone, linking this behavior to the stress system. Furthermore, these high-responding (HR) rats, in contrast to their low-responding (LR) counterparts, have a greater propensity to self-administer drugs. Thus, HR rats have been described as "novelty" seeking in that they are more active and explore novel stimuli more vigorously, despite the fact that this elicits in them high stress responses. In this study, we have further characterized the behavior of HR and LR rats in tests of anxiety and characterized their stress responses to either experimenter- or self-imposed stressors. We then investigated the physiological basis of these individual differences, focusing on stress-related molecules, including the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) in the context of the limbic-hypothalamo-pituitary adrenal axis. We have found that HR rats did not differ from LR in their basal expression of POMC in the pituitary. However, HR rats exhibited higher levels of CRH mRNA in the hypothalamic paraventricular nucleus but lower basal levels in the central nucleus of the amygdala. The basal expression of hippocampal MR is not different between HR and LR rats. Interestingly, the basal expression of hippocampal GR mRNA is significantly lower in HR than in LR rats. This low level of hippocampal GR expression in HR rats appears to be responsible, at least in part, for their decreased anxiety in exploring novelty. Indeed, the anxiety level of LR rats becomes similar to HR rats after the administration into the hippocampus of a GR antagonist, RU38486. These data indicate that basal differences in gene expression of key stress-related molecules may play an important role in determining individual differences in responsiveness to stress and novelty. They point to a new role of hippocampal GR, strongly implicating this receptor in determining individual differences in anxiety and novelty-seeking behavior.

Chronic corticosterone administration dose-dependently modulates Abeta(1-42)- and NMDA-induced neurodegeneration in rat magnocellular nucleus basalis.

The impact of glucocorticoids on beta-amyloid(1-42) (Abeta(1-42)) and NMDA-induced neurodegeneration was investigated in vivo. Abeta(1-42) or NMDA was injected into the cholinergic magnocellular nucleus basalis in adrenalectomized (ADX) rats, ADX rats supplemented with 25%, 100%, 2x100% corticosterone pellets, or sham-ADX controls. Abeta(1-42)- or NMDA-induced damage of cholinergic nucleus basalis neurones was assessed by quantitative acetylcholinesterase histochemistry. Plasma concentrations of corticosterone and cholinergic fibre loss after Abeta(1-42) or NMDA injection showed a clear U-shaped dose-response relationship. ADX and subsequent loss of serum corticosterone potentiated both the Abeta(1-42) and NMDA-induced neurodegeneration. ADX+25% corticosterone resulted in a 10-90 nM plasma corticosterone concentration, which significantly attenuated the Abeta(1-42) and NMDA neurotoxicity. ADX+100% corticosterone (corticosterone concentrations of 110-270 nM) potently decreased both Abeta(1-42)- and NMDA-induced neurotoxic brain damage. In contrast, high corticosterone concentrations of 310-650 nM potentiated Abeta(1-42)- and NMDA-triggered neurodegeneration. In conclusion, chronic low or high corticosterone concentrations increase the vulnerability of cholinergic cells to neurotoxic insult, while slightly elevated corticosterone levels protect against neurotoxic injury. Enhanced neurotoxicity of NMDA in the presence of high concentrations of specific glucocorticoid receptor agonists suggests that the corticosterone effects are mediated by glucocorticoid receptors.