Rise In Corticosterone Research Articles

A Rapid Release of Corticosteroid-Binding Globulin from the Liver Restrains the Glucocorticoid Hormone Response to Acute Stress

A strict control of glucocorticoid hormone responses to stress is essential for health. In blood, glucocorticoid hormones are for the largest part bound to corticosteroid-binding globulin (CBG), and just a minor fraction of hormone is free. Only free glucocorticoid hormone is able to exert biological effects, but little is known about its regulation during stress. We found, using a dual-probe in vivo microdialysis method, that in rats, the forced-swim stress-induced rise in free corticosterone (its major glucocorticoid hormone) is strikingly similar in the blood and in target compartments such as the subcutaneous tissue and the brain. However, in all compartments, the free corticosterone response was delayed by 20-30 min as compared with the total corticosterone response in the blood. We discovered that CBG is the key player in this delay. Swim stress evoked a fast (within 5 min) and profound rise in CBG protein and binding capacity in the blood through a release of the protein from the liver. Thus, the increase in circulating CBG levels after stress restrains the rise in free corticosterone concentrations for approximately 20 min in the face of mounting total hormone levels in the circulation. The stress-induced increase in CBG seems to be specific for moderate and strong stressors. Both restraint stress and forced swimming caused an increase in circulating CBG, whereas its levels were not affected by mild novelty stress. Our data uncover a new, highly dynamic role for CBG in the regulation of glucocorticoid hormone physiology after acute stress.

Membrane Mineralocorticoid but not Glucocorticoid Receptors of the Dorsal Hippocampus Mediate the Rapid Effects of Corticosterone on Memory Retrieval

This study was aimed at determining the type of the glucocorticoid membrane receptors (mineralocorticoid receptors (MRs) or glucocorticoid receptors (GRs)) in the dorsal hippocampus (dHPC) involved in the rapid effects of corticosterone or stress on memory retrieval. For that purpose, we synthesized corticosterone–3-O-carboxymethyloxime–bovine serum albumin conjugate (Cort–3CMO–BSA) conjugate (a high MW complex that cannot cross the cell membrane) totally devoid of free corticosterone, stable in physiological conditions. In a first experiment, we evidenced that an acute stress (electric footshocks) induced both a dHPC corticosterone rise measured by microdialysis and memory retrieval impairment on delayed alternation task. Both the endocrinal and cognitive effects of stress were blocked by metyrapone (a corticosterone synthesis inhibitor). In a second experiment, we showed that bilateral injections of either corticosterone or Cort–3CMO–BSA in dHPC 15 min before memory testing produced impairments similar to those resulting from acute stress. Furthermore, we showed that anisomycin (a protein synthesis inhibitor) failed to block the deleterious effect of Cort–3CMO–BSA on memory. In a third experiment, we evidenced that intra-hippocampal injection of RU-28318 (MR antagonist) but not of RU-38486 (GR antagonist) totally blocked the Cort–3CMO–BSA-induced memory retrieval deficit. In a fourth experiment, we demonstrated that RU-28318 administered 15 min before stress blocked the stress-induced memory impairments when behavioral testing occurred 15 min but not 60 min after stress. Overall, this study provides strong in vivo evidence that the dHPC membrane GRs, mediating the rapid and non-genomic effects of acute stress on memory retrieval, are of MR but not GR type.

Inhibition of food intake induced by acute stress in rats is due to satiation effects

Acute mild stress induces an inhibition of food intake in rats. In most studies, the cumulative daily food intake is measured but this only provides a quantitative assessment of ingestive behavior. The present study was designed to analyze the reduction in food intake induced by acute stress and to understand which behavioral and central mechanisms are responsible for it. Two different stressors, restraint stress (RS) and forced swimming stress (FSS), were applied acutely to male Wistar rats. We first measured corticosterone and ACTH in plasma samples collected immediately after acute RS and FSS in order to validate our stress models. We measured food intake after RS and FSS and determined meal patterns and behavioral satiety sequences. The expressions of CRF, NPY and POMC in the hypothalamus were also determined immediately after acute RS and FSS. The rise in corticosterone and ACTH levels after both acute RS and FSS validated our models. Furthermore, we showed that acute stress induced a reduction in cumulative food intake which lasted the whole day for RS but only for the first hour after FSS. For both stressors, this stress-induced food intake inhibition was explained by a decrease in meal size and duration, but there was no difference in ingestion speed. The behavioral satiety sequence was preserved after RS and FSS but grooming was markedly increased, which thus competed with, and could reduce, other behaviors, including eating. Lastly, we showed that RS induced an increase in hypothalamic POMC expression. These results suggest that acute stress may affect ingestive behavior by increasing satiation and to some extent by enhancing grooming, and this may be due to stimulation of the hypothalamic POMC neurons.

Protein kinase C phosphorylates the cAMP response element binding protein in the hypothalamic paraventricular nucleus during morphine withdrawal

Exposure to drugs of abuse or stress results in adaptation in the brain involving changes in gene expression and transcription factors. Morphine withdrawal modulates gene expression through various second-messenger signal transduction systems. Here, we investigated changes in activation of the transcription factor, cAMP-response element binding protein (CREB), in the hypothalamic paraventricular nucleus (PVN) and the kinases that may mediate the morphine withdrawal-triggered activation of CREB and the response of the hypothalamic-pituitary-adrenocortical (HPA) axis after naloxone-induced morphine withdrawal. The effects of morphine dependence and withdrawal, phosphorylated CREB (pCREB), corticotrophin-releasing factor (CRF) expression in the PVN and HPA axis activity were measured using immunoblotting, immunohistochemistry and radioimmunoassay in controls and in morphine-dependent rats, withdrawn with naloxone and pretreated with vehicle, calphostin C, chelerythrine (inhibitors of protein kinase C (PKC) or SL-327 [inhibitor of extracellular signal regulated kinase (ERK) kinase]. In addition, changes in PKCα and PKCγ immunoreactivity were measured after 60 min of withdrawal. In morphine-withdrawn rats, pCREB immunoreactivity was increased within CRF immunoreactive neurons in the PVN and plasma corticosterone levels were raised. SL-327, at doses that reduced the augmented pERK levels in the PVN, did not attenuate the rise in pCREB immunoreactivity or plasma corticosterone secretion. In contrast, PKC inhibition reduced the withdrawal-triggered rise in pCREB, pERK1/2 and corticosterone secretion. PKC mediated, in part, both CREB activation and the HPA response to morphine withdrawal. The ERK kinase/ERK pathway might not be necessary for either activation of CREB or HPA axis hyperactivity.

The newborn rat's stress system readily habituates to repeated and prolonged maternal separation, while continuing to respond to stressors in context dependent fashion

Adrenal corticosterone secretion of newborn mice rapidly desensitizes to repeated maternal absence. The present study investigated the effects of novelty exposure, maternal care and genotype on this phenomenon. Maternal separation (MS) took place on postnatal days ( pnd) 3–5. In Wistar rats, the degree of novelty in the MS-environment was varied by exposing pups to: (i) “home separation”: pups remained in the home cage; (ii) “novel separation”: pups were placed individually in a novel cage. Maternal care was recorded on pnd 1 to 4. To investigate the effect of genotype, we also examined Long Evans in the “home separation” condition. Basal and stress-induced ACTH and corticosterone levels were measured. Adrenal tyrosine hydroxylase (TH) and melanocortin receptor-2 (MCR-2) proteins served as markers for adrenal function. We show, in both rat strains, that the rise in plasma corticosterone induced by a single 8 h-MS on pnd 5 was abolished, when this separation procedure had also been performed on pnd 3 and 4. Habituation to maternal absence occurred irrespective of housing conditions. However, pups in the “home separation” condition received less maternal care upon reunion than those placed in the “novel separation”. These “home separation” pups appeared more responsive to a subsequent acute novelty-stressor, and their adrenal TH and MCR-2 were higher. Long Evans rats appeared more stress responsive than the Wistars, in the home separation condition. In conclusion, separation environment, maternal care and genotype do not affect adrenal desensitization to repeated 8 h-MS itself, but may modulate the adrenal stress-responsiveness of separated pups.

Elevated corticosterone in feathers correlates with corticosterone-induced decreased feather quality: a validation study

The newly described technique of extracting corticosterone (CORT) from bird feathers may serve as a less invasive, more integrated measure of a bird's stress response. Previous work indicated that elevated plasma CORT resulted in poorer quality feathers during molt. We tested the hypothesis that a direct link exists between plasma and feather CORT concentrations. We experimentally increased plasma CORT concentrations using implants and found that the corresponding rise in CORT could be detected in feathers grown during implantation. Furthermore, CORT levels in two feathers grown at the same time from the same bird were very consistent. These results provide evidence that elevated CORT is a causative factor in decreasing feather quality during molt. However, there remain technical details that suggest caution when interpreting data from CORT extracted from feathers. Different portions of a growing feather did not necessarily reflect changes in plasma CORT at the time different parts of the feather were forming, a standard pool of homogenized feathers indicated that sample mass affects measured feather CORT concentration, and different antibodies produced different measured CORT concentrations, leaving in doubt the exact steroid being assayed.

Benzodiazepine receptor antagonists reverse the effect of diazepam on plasma corticosterone in stressed rats.

The aim of this work has been to investigate the mechanism by which diazepam counteracts the plasma corticosterone rise induced by stress in rats. This effect is reversed by pretreatment with RO151788 and CGS8216. This observation suggests that the effect is mediated by benzodiazepine-specific receptors in brain.

Social defeat promotes specific cytokine variations within the prefrontal cortex upon subsequent aggressive or endotoxin challenges

Stressful experiences typically have short-lived neuroendocrine and neurochemical effects, but the processes leading to these biological alterations may be sensitized so that later challenges promote exaggerated responses. As stressors and immunogenic insults have both been associated with inflammatory immune variations within the brain, we assessed whether a social defeat stressor would result in augmented corticosterone release and mRNA expression of pro-inflammatory cytokines within the prefrontal cortex (PFC) upon later social defeat (sensitization) or endotoxin (lipopolysaccharide: LPS) challenges (cross-sensitization). In the absence of a prior stressor experience, the social defeat challenge did not affect prefrontal interleukin (IL)-1β or tumor necrosis factor (TNF)-α mRNA expression, but increased that of IL-6, whereas LPS increased the expression of each cytokine. Among mice that had initially been repeatedly defeated, IL-1β and TNF-α expression was enhanced after the social defeat challenge, whereas this was not evident in response to the LPS challenge. In contrast, the initial social defeat stressor had protracted effects in that increase of IL-6 expression was limited upon subsequent challenge with either social defeat or LPS. Previous social stressor experiences also limited the corticosterone rise ordinarily elicited by either social defeat or LPS treatment. It seems that a powerful stressor, such as social defeat, may have persistent effects on later corticosterone and cytokine responses to different types of stressful insults (social versus systemic challenges), but the nature of the effects varies with the specific process assessed.

Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory

BackgroundThe pharmacology of traumatic memory extinction has not been fully characterized despite its potential as a therapeutic target for established, acquired anxiety disorders, including post-traumatic stress disorder (PTSD). Here we examine the role of endogenous glucocorticoids in traumatic memory extinction. MethodsMale C57BL/6J mice were injected with corticosterone (10mg/kg, i.p.) or metyrapone (50mg/kg, s.c.) during re-activation of a contextual fear memory, and compared to vehicle groups (N=10–12 per group). To ensure that metyrapone was blocking corticosterone synthesis, we measured corticosterone levels following re-activation of a fear memory in metyrapone- and vehicle-treated animals. ResultsCorticosterone administration following extinction trials caused a long-lasting inhibition of the original fear memory trace. In contrast, blockade of corticosteroid synthesis with metyrapone prior to extinction trials enhanced retrieval and prevented extinction of context-dependent fear responses in mice. Further behavioral analysis suggested that the metyrapone enhancement of retrieval and prevention of extinction were not due to non-specific alterations in locomotor or anxiety-like behavior. In addition, the inhibition of extinction by metyrapone was rescued by exogenous administration of corticosterone following extinction trials. Finally, we confirmed that the rise in corticosterone during re-activation of a contextual fear memory was blocked by metyrapone. ConclusionsWe demonstrate that extinction of a classical contextual fear memory is dependent on endogenous glucocorticoid synthesis during re-activation of a fear memory. Our data suggest that decreased glucocorticoids during fear memory re-activation may contribute to the inability to extinguish a fear memory, thus contributing to one of the core symptoms of PTSD.

Neuroendocrine and behavioral response to amphetamine challenge after exposure to an organophosphorus pesticide

Exposure to various stressors is known to result in sensitization to psychostimulants, a state related to the psychostimulant dependence and addiction. It has been shown in some studies that the rise in corticosterone (CORT) concentration is indispensable for both the induction and the expression of behavioral sensitization. Therefore, it might be suspected that behavioral hyposensitivity to amphetamine (AMPH) is somehow related to a reduced CORT response to the psychostimulant subsequent to the chlorphenvinphos (CVP) intoxication. The male adult Wistar rats received single i.p. injections of CVP at the doses 0.5, 1.0 or 3.0 mg/kg b.w., or pure corn oil. CORT concentration was determined in samples of blood drawn from the tail vein before and then 30, 60, 180 min and 24 h after injection. The other rats were divided into two groups and tested, three weeks after the CVP injection for the effect of AMPH (0.5 mg/kg b.w. i.p.) on the serum CORT concentration. In addition, behavioral sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. 1) The stressor property of CVP was confirmed. The injection resulted in up to tenfold increase in the serum CORT concentration. The magnitude and duration of this response were dose-related. 2) Three weeks after the CVP exposure, the CORT response to AMPH was significantly increased. 3) The behavioral response to the psychostimulant, i.e. augmented locomotion, was significantly reduced compared to the control. The results confirm that CVP exposure causes behavioral hyposensitivity to AMPH. This effect, however, could not be ascribed to a diminished CORT response.

Corticosterone at fledging depends on nestling condition, not on parental desertion

Corticosterone at fledging depends on nestling condition, not on parental desertion Petra Quillfeldt1, Maud Poisbleau1,2, Ingrid Schwabl3, Olivier Chastel4, Juan F Masello11Max-Planck-Institut für Ornithologie, Vogelwarte Radolfzell, Radolfzell, Germany; 2University of Antwerp, Campus Drie Eiken, Department Biology – Ethology, Antwerp (Wilrijk), Belgium; 3Max-Planck-Institut für Ornithologie, Eberhard-Gwinner-Straße, Seewiesen, Germany; 4Centre d’Etudes Biologiques de Chizé, Centre National de la Recherche Scientifique, Deux-Sèvres, FranceAbstract: In some burrow-nesting birds, fledging is preceded by a strong rise in circulating corticosterone levels. Because the parents may desert nestlings in these species, this rise may be internally triggered or it may be a response to failing adult attention. We followed nestling thin-billed prions throughout the pre-fledging period in three seasons, 2005–2007. These seasons had contrasting oceanographic conditions, the sea surface temperature being warm in 2005, intermediate in the fledging period in 2006, and cold in 2007. Accordingly, the food availability, reflected in chick peak masses and begging rates, was low throughout 2005, intermediate during 2006, and high throughout 2007. We observed that most caring parents attended thin-billed prion nestlings until they were fledgings in the seasons of food scarcity during 2005 and 2006. In contrast, chicks were left alone for a mean of 4 days before fledging in 2007. The pre-fledging rise in corticosterone was lowest in the good year of 2007, even though most chicks were not attended during the pre-fledging period in that year. Our results thus indicate that CORT at fledging depends on nestling age and condition, not on parental desertion.Keywords: Pachyptila belcheri, Southwest Atlantic, fledging, corticosterone, independence

Augurin stimulates the hypothalamo‐pituitary‐adrenal axis via the release of corticotrophin‐releasing factor in rats

The functional characterization of secreted peptides can provide the basis for the development of novel therapeutic agents. Augurin is a recently identified secreted peptide of unknown function expressed in multiple endocrine tissues, and in regions of the brain including the hypothalamus. We therefore investigated the effect of hypothalamic injection of augurin on the hypothalamo-pituitary-adrenal (HPA) axis in male Wistar rats. Augurin was given as a single injection into the third cerebral ventricle (i.c.v.) or into the paraventricular nucleus (iPVN) of the hypothalamus. Circulating hormone levels were then measured by radioimmunoassay. The effect of augurin on the release of hypothalamic neuropeptides was investigated ex vivo using hypothalamic explants. The acute effects of iPVN augurin on behaviour were also assessed. i.c.v. injection of augurin significantly increased plasma ACTH and corticosterone, compared with vehicle-injected controls, but had no effect on other hypothalamo-pituitary axes hormones. Microinjection of lower doses of augurin into the PVN caused a similar increase in plasma ACTH and corticosterone, without significant alteration in behavioural patterns. Incubation of hypothalamic explants with increasing doses of augurin significantly elevated corticotrophin-releasing factor (CRF) and arginine vasopressin release. In vivo, peripheral injection of a CRF(1/2) receptor antagonist prevented the rise in ACTH and corticosterone caused by i.c.v. augurin injection. These data suggest that augurin stimulates the release of ACTH via the release of hypothalamic CRF. Pharmacological manipulation of the augurin system may therefore be a novel target for regulation of the HPA axis.

Association of the glucocorticoid receptor with STAT3, C/EBPβ, and the hormone‐responsive element within the rat haptoglobin gene promoter during the acute phase response

Upregulation of haptoglobin (Hp) expression in the rat during the acute phase (AP) response is the result of synergistic effects of IL-6-, IL-1beta-, and corticosterone-activated signaling pathways. IL-6 signaling terminates in cis-trans interactions of the Hp gene hormone-responsive element (HRE) with transcription factors STAT3 and C/EBPbeta. The aim of this study was to examine the unresolved molecular mechanism of glucocorticoid action. A 3-fold rise in serum corticosterone at 2 and 4 h of the AP response induced by turpentine administration preceded a 2.3-fold increase in the rate of Hp gene transcription at 12 h that was accompanied by a 4.8-fold increase in glucocorticoid receptor (GR), the appearance of an 86-kDa STAT3 isoform and 3.9-, 1.9-, and 1.7-fold increased amounts of 91-kDa STAT3, 35- and 42-kDa C/EBPbeta isoforms in the nucleus. These events resulted in 4.6- and 2.5-fold increased Hp levels in the liver and serum at 24 h. HRE affinity chromatography and immunoblot analysis revealed that maximal occupancy of the HRE with GR, STAT3, and C/EBPbeta at 12 h correlated with increased transcriptional activity of the Hp gene. Coimmunoprecipitation experiments showed that activated GR established de novo interaction with STAT3 isoforms while GR-C/EBPbeta interactions observed during basal transcription increased during the AP response. Computer analysis of the HRE disclosed two potential GR-binding sites: one overlapping STAT3, another adjacent to a C/EBPbeta-binding site. This finding and the experimental results suggest that activated GR through direct interactions with STAT3 and C/EBPbeta, participates in Hp gene upregulation as a transcriptional coactivator.

Increased stress-induced intra-hippocampus corticosterone rise associated with memory impairments in middle-aged mice

The present study investigates the relationships between hippocampal corticosterone concentrations and memory retrieval performance in stress and non-stress conditions, in both young (6 month-old) and middle-aged (16 month-old) mice. For this purpose, the time-course evolution of stress-induced corticosterone rise in the dorsal hippocampus (dHPC) was investigated in both young and middle-aged mice. In parallel, the evolution of memory retrieval patterns was assessed using a contextual serial discrimination task (CSD). Finally, metyrapone (corticosterone synthesis inhibitor) was administered in order to evaluate the stress-induced impact of corticosterone rise on contextual memory retrieval in middle-aged animals. Results showed that: (i) non-stressed middle-aged mice exhibited a memory retrieval pattern opposite to that of non-stressed young animals, but similar to that of stressed young mice; (ii) the impact of stress on memory performance was transient (90 min) in young, as compared to middle-aged mice (120 min); (iii) dHPC basal (non-stress) corticosterone level was significantly increased by ageing; (iv) acute stress induced a rapid (15 min) and transient (90 min) dHPC corticosterone rise in young mice, while exhibiting greater magnitude and duration (120 min) in middle-aged animals; and (v) both the stress-induced endocrinal and memory effects were blocked by metyrapone in young and middle-aged mice. Finally, to our knowledge, the present work is the first study to directly measure the corticosterone rise in the hippocampus following exposure to stress and to directly correlate the corticosterone changes in the hippocampus with memory performance in both young and middle-aged mice.

Glutamate receptor antagonist infused into the hypothalamic suprachiasmatic nuclei interferes with the diurnal fluctuations in plasma prolactin and corticosterone levels and injected into the mesencephalic dorsal raphe nucleus attenuates the suckling stimulus-induced release of prolactin of the rat

The aim of the present investigations was to examine the involvement of the rich glutamatergic innervation of the hypothalamic suprachiasmatic nucleus, a key structure in the control of circadian rhythms, in the regulation of the diurnal fluctuations in plasma prolactin and corticosterone, and to test the involvement of the glutamatergic innervation of the mesencephalic dorsal raphe nucleus in the prolactin response induced by the suckling stimulus. By means of a mini-pump a non-NMDA receptor antagonist (6-cyano-7- nitroquinoxaline-2,3-dione disodium, CNQX) was microinfused between the two suprachiasmatic nuclei for 3 days and on the third day blood samples were taken at different time points of the day. CNQX inhibited the afternoon rise in plasma prolactin and corticosterone. In lactating rats CNQX, similarly to the NMDA antagonist MK-801, microinjected into the dorsal raphe nucleus significantly attenuated the prolactin response to the suckling stimulus. The findings indicate that the glutamatergic innervation of the suprachiasmatic nuclei is involved in the diurnal fluctuations in plasma prolactin and corticosterone levels, and the glutamatergic innervation of the dorsal raphe nucleus has a prominent role in the mediation of the suckling stimulus to the hypothalamus.

Mediodorsal thalamic lesions block the stress-induced inversion of serial memory retrieval pattern in mice

This study examines the effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on serial contextual memory retrieval in non-stress and stress conditions. Independent groups of mice learned two successive contextual serial discriminations (D1 and D2) in a four-hole board. The discriminations differed each by the color and texture of the floor. Twenty-four hours later, memory testing occurred in independent groups of mice on one of the two floors of the initial acquisition session. Half of the subjects received three electric footschocks (0.9 mA, 2 s) 5 min prior to testing. Results showed that (i) stress induced a plasma corticosterone rise of same magnitude in sham-operated and MD-lesioned mice; (ii) non-stressed sham-operated mice accurately remembered D1 but not D2, whereas stressed sham-operated animals remembered D2 but not D1; (iii) non-stressed MD-lesioned mice exhibited a memory retrieval pattern similar to that observed in non-stressed sham-operated mice; (iv) however, the stress-induced inversion of the memory retrieval pattern was not observed in MD animals. The effects of MD lesions on memory retrieval in this task are similar to those observed in earlier studies in prefrontal cortex or amygdala-lesioned mice [Chauveau F, Piérard C, Coutan M, Drouet I, Liscia P, Béracochéa D. Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory pattern in mice. Neurobiol Learn Mem 2008;90:395–403]; they are however in sharp contrast with mice exhibiting hippocampal lesions [Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress condition. Neurobiol Learn Mem; in press; Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus; in press]. Overall, the present findings highlight the involvement of the MD in an AMG/PFC system mediating the rapid effects of stress on serial memory retrieval.

Rapid stress‐induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern

We previously showed that an acute stress (electric footshocks) induced both a rapid plasma corticosterone rise and a reversal of serial memory retrieval pattern in a contextual serial discrimination (CSD) task. This study is aimed at determining (i) if the rapid stress effects on CSD performance are mediated by the hippocampus; (ii) if hippocampal corticosterone membrane receptor activation is involved in the rapid stress effects on CSD performance. In experiment 1, microdialysis in the dorsal hippocampus (dHPC) was used to measure the stress-induced corticosterone rise; in parallel, the effect of acute stress on CSD performance was evaluated. In addition, the functional involvement of corticosterone in the behavioral effects of stress was assessed by administering metyrapone, a corticosterone synthesis inhibitor, before stress. In experiment 2, the involvement of hippocampal corticosterone membrane receptors in the stress-induced reversal of CSD performance was studied by injecting corticosterone-bovine serum albumin (BSA) (a membrane-impermeable complex) in the dHPC in non stressed mice. Results showed that (i) the acute stress induced a rapid (15 min) and transitory (90 min) corticosterone rise into the hippocampus dHPC, and a reversal of serial memory retrieval pattern; (ii) both the endocrinal and memory stress-induced effects were blocked by metyrapone; (iii) corticosterone-BSA injection into the dHPC in non stressed mice mimicked the effects of stress on serial retrieval pattern. Overall, our study is first to show that (i) a rapid stress-induced corticosterone rise into the dHPC transitorily reverses serial memory retrieval pattern and (ii) hippocampal corticosterone membrane receptors activation is involved in the rapid effects of acute stress on serial memory retrieval.

Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic–pituitary–adrenal axis via estrogen receptor alpha within the hypothalamus

Numerous studies have established a link between individuals with affective disorders and a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, most notably characterized by a reduced sensitivity to glucocorticoid negative (−) feedback. Furthermore there is a sex difference in the etiology of mood disorders with incidence in females being two to three times that of males, an association that may be a result of the influence of estradiol (E2) on HPA axis function. In these studies, we have examined the effect of E2 on glucocorticoid-mediated HPA axis (−) feedback during both the diurnal peak and the stress-induced rise in corticosterone (CORT). Young adult female Sprague–Dawley (SD) rats were ovariectomized (OVX) and 1 week later treated subcutaneous (s.c.) with oil or estradiol benzoate (EB) for 4 days. On the 4th day of treatment, animals were injected with a single dose of dexamethasone (DEX), or vehicle. EB treatment significantly increased the evening elevation in CORT and the stress-induced rise in CORT. In contrast, DEX treatment reduced the diurnal and stress induced rise in CORT and adrenocorticotropic hormone (ACTH), and this reduction was not apparent following co-treatment with EB. To determine a potential site of E2's action, female SD rats were OVX and 1 week later, wax pellets containing E2, the estrogen receptor beta (ERβ) agonist diarylpropionitrile (DPN), or the estrogen receptor alpha (ERα) agonist propylpyrazoletriol (PPT), was implanted bilaterally and dorsal to the paraventricular nucleus of the hypothalamus (PVN). Seven days later, animals were injected s.c. with a single dose of DEX, or vehicle to test for glucocorticoid-dependent (−) feedback. Results show that E2 and PPT increased, while DPN decreased the diurnal peak and stress-induced CORT and ACTH levels as compared to controls. Furthermore, E2 and PPT impaired the ability of DEX to inhibit both the diurnal and the stress-induced rise in CORT and ACTH, whereas DPN had no effect. Neuronal activation was measured by c-fos mRNA expression within the PVN following restraint. E2 and PPT increased c-fos mRNA, and impaired the normal DEX suppression of neuronal activation in the PVN. Taken together, these data indicate that estradiol causes a dysregulation of HPA axis (−) feedback as evidenced by the inability of DEX to suppress diurnal and stress-induced CORT and ACTH secretion. Additionally, the ability of E2 to inhibit glucocorticoid (–) feedback occurs specifically via ERα acting at the level of the PVN.

Selectively Filtering Short Wavelengths Attenuates the Disruptive Effects of Nocturnal Light on Endocrine and Molecular Circadian Phase Markers in Rats

Various physiological processes exhibit a circadian rhythm synchronized to the geophysical light/dark cycle. Our study using a rat model demonstrated that exposure to light at night suppressed the expected nocturnal rise in melatonin, increased plasma corticosterone, and disrupted core clock gene expression in the hypothalamus and the adrenal gland. These effects were prevented by filtration of a 10-nm bandwidth of light between 470 and 480 nm, whereas filtration of light between 452 and 462 nm prevented the rise of corticosterone without restoring normal melatonin secretion or hypothalamic clock gene expression. This is the first demonstration of a wavelength dependency of glucocorticoid secretion and clock gene expression. Our results in an animal model suggest that filtering a narrow bandwidth of light from nocturnal lighting may efficiently attenuate overall disruption of circadian endocrine rhythms and clock gene expression in the hypothalamus and adrenal gland. Because a narrow bandwidth of light is filtered, the color distribution of the illumination source is not altered, and this may be of practical importance for potential future studies in shift workers.

Pharmacokinetic/Pharmacodynamic Modeling of Corticosterone Suppression and Lymphocytopenia by Methylprednisolone in Rats

Adrenal suppression and lymphocytopenia are commonly monitored pharmacological responses during systemic exposure to exogenously administered corticosteroids. The pharmacodynamics of plasma corticosterone (CS) and blood lymphocytes were investigated in 60 normal rats which received either 50 mg/kg methylprednisolone (MPL) or vehicle intramuscularly. Blood samples were collected between 0.5 and 96h following treatment. Plasma CS displayed a transient suppression with re-establishment of a normal circadian rhythm 24h following drug treatment. An indirect response model with suppression of production well captured plasma CS profiles. An early stress-induced rise in CS was also factored into the model. Blood lymphocyte numbers exhibited a sharp decline and then returned to a new circadian rhythm which was half of the original baseline level. An integrated pharmacodynamic (PD) model with inhibition of lymphocyte trafficking from tissue to blood by both MPL and CS and induction of cell apoptosis by MPL reasonably captured this lymphocytopenia. Rats and humans differ in lymphocyte responses with humans showing full recovery of baselines. Modeling provides a valuable tool in quantitative assessment of dual, complex drug responses.