Showing papers on "Corticosterone published in 2005"

Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone

Abstract: The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways.

The potential influence of maternal stress hormones on development and mental health of the offspring.

Abstract: Recent studies in humans suggest that alterations in the activity of the neuroendocrine system mediate the effects of psychosocial stress on fetal development and birth outcome. Chronic maternal distress compromises the normal regulation of hormonal activity during pregnancy and elevates free circulating corticotrophin-releasing hormone (CRH), probably of placental origin, before the normal increase occurs at term. Excess CRH, and other hormones like cortisol and met-enkephalin that pass through the placenta, could precipitate preterm labor, reduce birth weight and slow growth rate in prenatally stressed infants. CRH and/or cortisol have also been associated with impaired fetal habituation to stimuli and temperamental difficulties in infants. These changes may result from actions of the hormones on their receptors in the fetal limbic system. In the rat, gestational stress and excess maternal and fetal plasma corticosterone cause downregulation of fetal glucocorticoid (GR) and mineralocorticoid (MR) receptors and impair the feedback regulation of the hypothalamic-pituitary adrenal (HPA) axis in infancy and adulthood. The impairment in HPA axis activity can be prevented by maternal adrenalectomy and mimicked by administration of glucocorticoids. Gestational stress also increases CRH activity in the amygdala and the incidence of anxiogenic and depressive-like behavior in rats and non-human primates, which can be ameliorated by CRH antagonists. Excess amounts of CRH and cortisol reaching the human fetal brain during periods of chronic maternal stress could alter personality and predispose to attention deficits and depressive illness through changes in neurotransmitter activity.

Exposure to chronic stress downregulates corticosterone responses to acute stressors

Abstract: We used captive European starlings (Sturnus vulgaris) to test whether corticosterone responses differed in birds held under normal laboratory conditions or conditions of chronic stress. Surprisingly, both basal corticosterone concentrations and corticosterone responses to acute stress were significantly reduced when birds were chronically stressed. To determine the mechanism underlying this reduced response, animals under both conditions were injected with lactated Ringer's solution (control), adrenocorticotropin (ACTH), arginine vasotocin (AVT), or dexamethasone (DEX). ACTH increased corticosterone concentrations above stress-induced levels in both cases, although maximum responses were lower in chronically stressed birds. AVT did not augment the corticosterone response under nonchronically stressed conditions, but it did under chronically stressed conditions. DEX reduced maximal corticosterone concentrations in both cases. Neither ovine nor rat corticotropin-releasing factor (CRF) altered normal stress responses. These data indicate that changes in responsiveness of the hypothalamic-pituitary-adrenal axis to ACTH and AVT serve to downregulate corticosterone responses during chronic stress. Furthermore, these data lead to the following hypothesis: ACTH output from the pituitary limits maximum corticosterone concentrations under normal conditions, but reduced AVT release from the hypothalamus regulates lower corticosterone concentrations under chronic stress conditions.

Mild, Short-term Stress Alters Dendritic Morphology in Rat Medial Prefrontal Cortex

Abstract: Prefrontal cortex is a target for glucocorticoids, shows neurochemical changes in response to stress and mediates many of the behaviors that are altered by chronic corticosterone administration. Three weeks of either daily corticosterone injections or 3 h daily restraint stress result in dendritic changes in pyramidal neurons in medial prefrontal cortex. Interestingly, vehicle injection results in similar but less pronounced changes. Thus, the mild stress of daily injections alone may alter morphology of medial prefrontal cortex, suggesting an exquisite sensitivity to chronic stress. To further examine this morphological sensitivity, we assessed the effect of 1 week of daily brief restraint stress on dendritic morphology in medial prefrontal cortex. Male rats were restrained 10 min per day for one week, handled daily or left unhandled. Rats were then overdosed and brains were stained using a Golgi--Cox procedure. Layer II--III pyramidal neurons in medial prefrontal cortex were drawn and dendritic morphology was quantified. One week of daily brief restraint resulted in selective remodeling of apical dendrites, with atrophy of up to 22--35% in distal branches and sparing of proximal branches. This pattern of reorganization is similar to that seen after either corticosterone injections or 3 weeks of daily 3 h restraint stress. Thus, the stress-induced dendritic changes in medial prefrontal cortex occur rapidly, and in response to a mild stressor.

Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors

Abstract: Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 μg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

Stress hormone and male reproductive function

Abstract: 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.

Endocrinological and catecholaminergic alterations during sleep deprivation and recovery in male rats.

Abstract: Since previous data of our group showed increased concentrations in HPA axis hormones in sleep deprived rats, we hypothesized that this augmentation could produce effects in other hormonal systems, particularly in the sexual system. Considering that little is known about how the hormonal system changes during the recovery period after sleep deprivation (SD), our objective was to examine from what point SD alters sexual and stress-related hormones along with plasma catecholamine concentrations during 4 days. We also sought to verify the time course of their recovery after an equivalent period of recovery sleep. Rats were deprived of sleep by the platform technique for 1-4 days and were allowed to recover for the same period. Plasma catecholamines [dopamine (DA) and noradrenaline (NOR)], testosterone, estrone, progesterone, prolactin, corticosterone and adrenocorticotropic hormone (ACTH) concentrations were measured. Comparisons between groups showed that the SD procedure used in the present study produced marked alterations in almost all studied hormones from 24 h of SD, except for estrone and prolactin (which required 96 h of SD to become altered). Testosterone and estrone decreased, whereas progesterone, prolactin, corticosterone, ACTH, DA and NOR increased. During recovery period, progesterone, prolactin and corticosterone concentrations returned to control levels, whereas testosterone, estrone, NOR and DA did not. In addition, after 48 h of recovery ACTH and NOR decreased below control concentrations, remaining low until 96 h of sleep recovery. Thus, SD showed long lasting, differential effects upon these neurochemicals suggesting that each has its own pattern of responses to SD as well as variable periods of recovery.

Neonatal Infection-Induced Memory Impairment after Lipopolysaccharide in Adulthood Is Prevented via Caspase-1 Inhibition

Abstract: We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1–24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1β (IL-1β) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1β, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1β in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.

Mineralocorticoid versus Glucocorticoid Receptor Occupancy Mediating Aldosterone-Stimulated Sodium Transport in a Novel Renal Cell Line

Abstract: Aldosterone controls sodium balance by regulating an epithelial sodium channel (ENaC)-mediated sodium transport along the aldosterone-sensitive distal nephron, which expresses both mineralocorticoid (MR) and glucocorticoid receptors (GR). Mineralocorticoid specificity is ensured by 11β-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR. The fractional occupancy of MR and GR by aldosterone mediating the sodium transport response in the aldosterone-sensitive distal nephron cannot be studied in vivo . For answering this question, a novel mouse cortical collecting duct cell line (mCCD cl1 ), which expresses significant levels of MR and GR and a robust aldosterone sodium transport response, was used. Aldosterone elicited a biphasic response: Low doses (K 1/2 = approximately 0.5 nM) induced a transient and early increase of sodium transport (peaking at 3 h), whereas high doses (K 1/2 = approximately 90 nM) entailed an approximately threefold larger, long-lasting response. At 3 h, the corticosterone dose-response curve was shifted to the right compared with that of aldosterone by more than two log concentrations, an effect that was fully reverted in the presence of the 11β-hydroxysteroid dehydrogenase type 2 inhibitor carbenoxolone. Low doses of dexamethasone (0.1 to 1 nM) failed to induce an early response, but high doses elicited a long-lasting response (K 1/2 = approximately 8 nM), similar to that observed for high aldosterone concentrations. Equilibrium binding assays showed that both aldosterone and corticosterone bind to a high-affinity, low-capacity site, whereas dexamethasone binds to one site. Within the physiologic range of aldosterone concentrations, sodium transport is predicted to be controlled by MR occupancy during circadian cycles and by MR and GR occupancy during salt restriction or acute stress.

Mineralocorticoid receptors: distribution and activation.

Abstract: Mineralocorticoid receptors (MR) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone ≥ aldosterone = cortisol), and are found in both Na+ transporting epithelia (e.g. kidney, colon) and nonepithelial tissues (e.g. heart, brain). MR evolved before aldosterone synthase, consistent with their acting in nonepithelial tissues as high affinity glucocorticoid receptors, essentially always occupied by normal levels of endogenous glucocorticoids. In epithelial tissues the enzyme 11β hydroxysteroid dehydrogenase Type 2 (11βHSD2) allows aldosterone to selectively activate MR, by converting cortisol to cortisone and NAD to NADH. 11βHSD2 debulks intracellular cortisol by 90%, to levels ∼10-fold those of aldosterone, so that when the enzyme is operating most epithelial MR are occupied but not activated by cortisol. When intracellular redox state is changed—by inhibition of 11β HSD2, generation of reactive oxygen species, or intracellular introduction of oxidised glutathione (GSSG)—cortisol changes from an MR antagonist to an MR agonist. This bivalent activity of cortisol appears to underlie the therapeutic efficacy of MR blockade in heart failure (RALES, EPHESUS) and in essential hypertension, providing a rationale for MR blockade in cardiovascular disease not characterized by elevated aldosterone levels. Its wider (patho)physiologic implications, particularly for neurobiology, remain to be explored.

CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH

Abstract: The response to systemic stress is organized along the hypothalamic-pituitary-adrenal axis (HPA), whereas the response to a peripheral stress (solar radiation) is mediated by epidermal melanocytes (cells of neural crest origin) responsible for the pigmentary reaction. Melanocytes express proopiomelanocortin (POMC), corticotropin-releasing hormone (CRH), and CRH receptor-1 (CRH-R1) and can produce corticosterone. In the present study, incubation of normal epidermal melanocytes with CRH was found to trigger a functional cascade structured hierarchically and arranged along the same algorithm as in the HPA axis: CRH activation of CRH-R1 stimulated cAMP accumulation and increased POMC gene expression and production of ACTH. CRH and ACTH also enhanced production of cortisol and corticosterone, and cortisol production was also stimulated by progesterone. The chemical identity of the cortisol was confirmed by liquid chromatography-mass spectrometry without mass spectrometry-mass spectrometry analyses. POMC gene silencing abolished the stimulatory effect of CRH on corticosteroid synthesis, indicating that this is indirect and mediated via production of ACTH. Thus the melanocyte response to CRH is highly organized along the same functional hierarchy as the HPA axis. This pattern demonstrates the fractal nature of the response to stress with similar activation sequence at the single-cell and whole body levels.

Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome.

Abstract: In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11β-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes.

BDNF protects against stress-induced impairments in spatial learning and memory and LTP.

Abstract: The present study investigated whether infusion of brain-derived neurotrophic factor (BDNF) could ameliorate stress-induced impairments in spatial learning and memory as well as hippocampal long-term potentiation (LTP) of rats. Chronic immobilization stress (2 h/day x 7 days) significantly impaired spatial performance in the Morris water maze, elevated plasma corticosterone, and attenuated LTP in hippocampal slices from these animals as compared with normal control subjects. BDNF was infused into the left hippocampus (0.5 mul/h) for 14 days, beginning 7 days before the stress exposure. The BDNF group was protected from the deleterious effects of stress and performed at a level indistinguishable from normal control animals despite the presence of elevated corticosterone. BDNF alone and sham infusions had no effect on performance or LTP. These results demonstrate that spatial learning and memory, and LTP, a candidate neural substrate of learning and memory, are compromised during chronic stress, and may be protected by BDNF administration.

Neural circuitry in the regulation of adrenal corticosterone rhythmicity

Abstract: Adrenal cortical secretion of glucocorticoids is an essential adaptive response of an organism to stress Although the hypothalamic-pituitary-adrenal axis regulates the adrenal cortex via release of ACTH, there is strong evidence supporting a role for sympathetic innervation in modulating adrenal glucocorticoid secretion The dissociation between changes in ACTH and glucocorticoids under non-stress and stress conditions has reinforced the concept that neural control of the adrenal cortex acts to modulate steroidogenic responses to circulating ACTH A dual control of the adrenal cortex has been implicated in the prominent circadian rhythm in glucocorticoids However, the central neural substrate for circadian changes in glucocorticoids that are mediated by peripheral neural innervation of the adrenal cortex has not been conclusively delineated The hypothesis to be addressed is that neurons in the paraventricular nucleus of the hypothalamus receive input from the suprachiasmatic nucleus and project to sympathetic preganglionic neurons in the spinal cord to provide inhibitory and excitatory input to the adrenal cortex that drives the circadian rhythm This review examines anatomical and physiological evidence that forms the basis for this putative neural circuit

Maternal influences on adult stress and anxiety-like behavior in C57BL/6J and BALB/cJ mice: a cross-fostering study.

Abstract: The quality of maternal care during early life has a dramatic impact on later stress reactivity and anxiety. Two inbred mouse strains, C57BL/6J and BALB/cJ, differ in levels of maternal care, stress reactivity, and anxiety-like behavior in adulthood. However, the relative contribution of early environmental factors and genetic predisposition to differences in these strains is not known. Maternal care, plasma corticosterone levels, emotionality, and hippocampal and paraventricular nucleus (PVN) glucocorticoid receptor mRNA levels were measured in adult C57BL/6J and BALB/cJ mice. Litters were then cross-fostered and anxiety-like behavior and stress reactivity was assessed in adulthood. Significantly less maternal care and elevated stress-induced corticosterone and emotionality was observed in BALB/cJ compared to C57BL/6J mice. Yet, no strain differences were found in hippocampal or paraventricular nucleus glucocorticoid receptor mRNA levels. Cross-fostering did alter anxiety-like behavior and basal corticosterone levels, which suggests that while genetic differences account for some of the variations between these two strains early rearing conditions also contribute.

Corticosterone Slowly Enhances Miniature Excitatory Postsynaptic Current Amplitude in Mice CA1 Hippocampal Cells

Abstract: Corticosteroid hormones are released in high amounts after stress and bind to intracellular receptors in the brain, which in activated form function as transcription factors. We here tested the effect of a high dose of corticosterone on AMPA-receptor-mediated transmission in the CA1 hippocampal area, which is enriched in corticosteroid receptors. To focus on slow gene-mediated effects of the hormone, excitatory postsynaptic currents were measured at least 1 h after a brief application of 100 nM corticosterone to slices from adrenally intact adult mice. The amplitude but not frequency of miniature postsynaptic excitatory currents was found to be significantly enhanced. These effects were mimicked by 100 nM RU 28362, a selective agonist for intracellular glucocorticoid receptors. Evoked AMPA responses at the single cell were significantly enhanced when measured 2-4 h after application of 100 nM corticosterone, but not at earlier moments nor with a longer delay. In summary, the present results show that activation of hippocampal glucocorticoid receptors induces a slow enhancement of AMPA-receptor-mediated responses, at the single-cell level.

Aldosterone biosynthesis, regulation, and classical mechanism of action.

Abstract: Circulating aldosterone is principally made in the glomerulosa zone of the adrenal cortex by a series of enzyme steps leading to the conversion of cholesterol to aldosterone. Uniquely, aldosterone's production is regulated at two critical enzyme steps: (1) early in its biosynthetic pathway (the conversion of cholesterol to pregnenolone cholesterol side chain cleavage enzyme) and (2) late (the conversion of corticosterone to aldosterone by aldosterone synthase). A variety of factors modify aldosterone secretion--the most important are angiotensin II (AngII), the end-product of the renin-angiotensin system (RAS), and potassium. However ACTH, neural mediators and natriuretic factors also contribute at least over the short run. Aldosterone's classical epithelial effect is to increase the transport of sodium across the cell in exchange for potassium and hydrogen ions. Although still controversial, there is an increasing body of data that supports the hypothesis that aldosterone can be synthesized in tissues outside of the adrenal cortex, specifically in the heart and the vasculature. Aldosterone's biosynthesis appears to be regulated in these tissues similar to what occurs in the adrenal cortex. The role of this extra adrenal aldosterone production in health and disease is as of yet undetermined.

Chronic mild stress induces behavioral and physiological changes, and may alter serotonin 1A receptor function, in male and cycling female rats

Abstract: Interactions among stress, serotonin 1A (5-HT1A) receptors, and the hypothalamic–pituitary–adrenocortical (HPA) system have been proposed to influence the development of depression in humans. The investigation of depression-relevant behaviors and physiological responses to environmental stressors in animal models of depression may provide valuable insight regarding these mechanisms. The purpose of these experiments was to investigate the interactions among central 5-HT1A receptors, endocrine function, and behavior in an animal model of depression, chronic mild stress (CMS). The current study examined behavioral responses to a pleasurable stimulus (sucrose), estrous cycle length (in female rats), and plasma hormone levels following systemic administration of a selective 5-HT1A receptor agonist [(+)8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT); 40 μg/kg, s.c.; administered 15 min prior to sacrifice], in male and female rats exposed to 4 weeks of CMS. Four weeks of CMS produced a reduction in the intake of 1% sucrose (anhedonia), as well as attenuated adrenocorticotropic hormone (ACTH) responses to 8-OH-DPAT in both male and female rats (22 and 18% lower than the control groups, respectively). Corticosterone and oxytocin responses to 8-OH-DPAT were not altered by exposure to CMS. In female rats, CMS induced a lengthening of the estrous cycle by ∼40%. CMS produces minor HPA disruptions along with behavioral disruptions. Alterations in 5-HT1A receptor function in specific populations of neurons in the central nervous system may be associated with the CMS model. The current findings contribute to our understanding of the relations that stress and neuroendocrine function have to depressive disorders.

Modulation of motor function by stress: a novel concept of the effects of stress and corticosterone on behavior.

Abstract: Stress and stress hormones affect a variety of behaviors and cognitive abilities. The influences of stress and glucocorticoids on motor function, however, have not been characterized although the presence of glucocorticoid receptors in the motor system has been documented. Here we demonstrate that stress and the stress hormone corticosterone influence motor system function in rats. Groups of adult female Long-Evans rats underwent either a daily stress-inducing procedure (immobilization or swimming in cold water) or oral corticosterone treatment. While these treatments continued, animals were tested in skilled reaching and skilled walking tasks for a period of 2 weeks. Both acute (day 1) and chronic (day 14) stress and corticosterone treatment reduced skilled movement accuracy in reaching and walking and increased performance speed. Furthermore, both chronic stress and chronic corticosterone treatment altered skilled movement patterns in the reaching task. These findings indicate that stress modulates motor system function and that these effects are partially mediated by glucocorticoids. To examine whether stress-induced changes might also derive from enhanced emotionality, rats were treated with the benzodiazepine diazepam. Based on an inverted U-shaped dose-response relationship, a moderate dose of diazepam significantly improved reaching success while at the same time reducing corticosterone levels. Thus, stress-associated emotional responses such as anxiety might account for diminished movement accuracy. These results suggest that stress affects the motor system both directly via hormonal changes and indirectly via changes in emotionality. These findings are discussed with respect to the role of stress in motor system function and movement disorders.

Relation between the Hypothalamic-Pituitary-Thyroid (HPT) axis and the Hypothalamic-Pituitary-Adrenal (HPA) axis during repeated stress

Abstract: Previous work has indicated that acute and repeated stress can alter thyroid hormone secretion. Corticosterone, the end product of hypothalamic-pituitary-adrenal (HPA) axis activation and strongly reg

Aldosterone as a cardiovascular risk factor

Abstract: Aldosterone exerts cardiovascular effects by influencing epithelial fluid and electrolyte excretion, and thus blood volume and pressure. Mineralocorticoid receptors (MR) are found in epithelial and non-epithelial tissues (vessel walls, heart, brain), with high affinity for aldosterone and physiological glucocorticoids cortisol and corticosterone. MR blockade by spironolactone or eplerenone favorably affects cardiovascular outcomes. In some situations (primary aldosteronism, experimental mineralocorticoid administration) activation of cardiovascular MR reflects aldosterone levels inappropriate for salt status. In others (heart failure, essential hypertension) aldosterone and Na + status are often normal pretreatment; cardiovascular MR may thus be activated by normal glucocorticoid levels after tissue damage and reactive oxygen species generation. Therefore, although unilateral adrenalectomy is preferred therapy for unilateral aldosterone-producing adenoma or hyperplasia, MR blockade may be useful in cardiovascular diseases where aldosterone levels are normal.

Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus.

Abstract: New neurons are produced continually in the dentate gyrus of the hippocampus. Numerous factors modulate the rate of neuron production. One of the most important is the adrenal-derived corticoids. Raised levels of corticoids suppress proliferation of progenitor cells, while removal of corticoids by adrenalectomy reverses this. The exact mechanisms by which corticoids mediate such regulation are unknown, but corticoids are believed to act through the receptors for mineralocorticoids (MR) and glucocorticoids (GR). Previous reports regarding the roles of these receptors in regulating cell proliferation came to contrasting conclusions. Here we use both agonists and antagonists to these receptors in adult male rats to investigate and clarify their roles. Blockade of MR with spironolactone in adrenalectomised male rats implanted with a corticosterone pellet to reproduce basal levels enhanced proliferation, whereas treatment with the GR antagonist mifepristone had no effect. However, mifepristone reversed the suppressive effect of additional corticosterone in intact rats. Both aldosterone and RU362, agonists of MR and GR, respectively, reduced proliferation in adrenalectomised rats, and combined treatment with both agonists had an additional suppressive action. These results clearly show that occupancies of both receptors act in the same direction on progenitor proliferation. The existence of two receptors with different affinities for corticoids may ensure that proliferation of progenitor cells in the adult dentate gyrus is regulated across the range of adrenal corticoid activity, including both basal and stressful contexts. Although a small proportion of newly formed cells may express GR and MR, corticosterone probably regulates proliferation indirectly through other local cells.

Frequent serial fecal corticoid measures from rats reflect circadian and ovarian corticosterone rhythms

Abstract: The circadian glucocorticoid rhythm provides important information on the functioning of the hypothalamicpituitary-adrenal axis in individuals. Frequent repeated blood sampling can limit the kinds of studies conducted on this rhythm, particularly in small laboratory rodents that have limited blood volumes and are easily stressed by handling. We developed an extraction and assay protocol to measure fecal corticosterone metabolites in repeated samples collected from undisturbed male and female adult Sprague–Dawley rats. This fecal measure provides a noninvasive method to assess changes in corticosterone within a single animal over time, with sufficient temporal acuity to quantify several characteristics of the circadian rhythm: e.g. the nadir, acrophase, and asymmetry (saw-tooth) of the rhythm. Males excreted more immunoreactive fecal corticoids than did females. Across the estrous cycle, females produced more fecal corticoids on proestrus (the day of the preovulatory luteinizing hormone surge) than during estrus or metestrus. These results establish a baseline from which to study environmental, psychological, and physiological disturbances of the circadian corticosterone rhythm within individual rats.

Roles of stress hormones in food intake regulation in anuran amphibians throughout the life cycle

Abstract: Towards understanding the ontogeny of energy balance regulation in vertebrates we analyzed the responses of corticotropin-releasing factor (CRF) and corticosterone to food deprivation in the Western spadefoot toad (Spea hammondii) at three developmental stages: premetamorphic tadpole, prometamorphic tadpole, and juvenile. Corticosterone responses to 5 days of food deprivation varied among developmental stages. Both pre- and prometamorphic tadpoles increased whole-body corticosterone content with food deprivation, but the magnitude of the response of premetamorphic tadpoles was significantly greater. By contrast, juvenile toads decreased plasma corticosterone concentration. Similarly, brain CRF peptide content tended to increase in food-deprived tadpoles but did not change in food-deprived juveniles. Therefore, there is an ontogenetic difference in the way the hypothalamic-pituitary-interrenal (HPI) axis responds to food deprivation in amphibians. In tadpoles, the HPI axis is activated in response to fasting as is seen in birds and mammals, and may be associated with mobilization of stored fuels and increased foraging. Juvenile toads do not respond to food deprivation by activating the HPI axis, but instead pursue a strategy of energy conservation that involves a reduction in plasma corticosterone concentration.