Increased Plasma Glucocorticoid Research Articles

Transient Elevation of Plasma Glucocorticoids Supports Psilocybin-Induced Anxiolysis in Mice.

While correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have anxiolytic-like effects in C57BL/6 male mice at 4 h after treatment. These effects were not altered by pretreatment with a 5-HT2A antagonist but were blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. Anxiolytic-like effects were also observed at 4 h following treatment with the nonpsychedelic 5-HT2A agonist lisuride at a dose causing a similar increase in plasma glucocorticoids as that seen with psilocybin, as well as following stress-induced (via repeated injection) glucocorticoid release alone. Psilocybin's anxiolytic-like effects persisted at 7 days following administration. The long-term anxiolytic effects of psilocybin were lost when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute, resolvable psilocybin-induced glucocorticoid release drives the postacute anxiolytic-like effects of psilocybin in mice and that its long-term anxiolytic-like effects can be abolished in the presence of chronically elevated plasma glucocorticoid elevations.

Cholestasis-associated glucocorticoid overexposure does not increase atherogenesis.

Chronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid levels. Here, we determined - in a preclinical setting - whether the chronic presence of cholestatic liver disease also induces a concomitant negative impact on atherosclerosis susceptibility. Hereto, regular chow diet-fed atherosclerosis-susceptible hypercholesterolemic apolipoprotein E (APOE)-knockout mice were treated with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) for 8 weeks. ANIT exposure induced the development of fibrotic cholestatic liver disease as evident from collagen deposits and compensatory bile duct hyperproliferation within the liver and the rise in plasma levels of bilirubin (+60%; P < 0.01) and bile acids (10-fold higher; P < 0.01). Adrenal weights (+22%; P < 0.01) and plasma corticosterone levels (+72%; P < 0.01) were increased in ANIT-treated mice. In contrast, atherosclerosis susceptibility was not increased in response to ANIT feeding, despite the concomitant increase in plasma free cholesterol (+30%; P < 0.01) and cholesteryl ester (+42%; P < 0.001) levels. The ANIT-induced hypercorticosteronemia coincided with marked immunosuppression as judged from the 50% reduction (P < 0.001) in circulating lymphocyte numbers. However, hepatic glucocorticoid signaling was not enhanced after ANIT treatment. It thus appears that the immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effect under cholestatic disease conditions. In conclusion, we have shown that cholestatic liver disease-associated endogenous glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE-knockout mice. Our studies provide novel preclinical evidence for the observations that the hypercholesterolemia seen in cholestatic human subjects does not translate into a higher risk for atherosclerotic cardiovascular disease.

Biomarkers for classification and class prediction of stress in a murine model of chronic subordination stress.

Selye defined stress as the nonspecific response of the body to any demand and thus an inherent element of all diseases. He reported that rats show adrenal hypertrophy, thymicolymphatic atrophy, and gastrointestinal ulceration, referred to as the stress triad, upon repeated exposure to nocuous agents. However, Selye’s stress triad as well as its extended version including reduced body weight gain, increased plasma glucocorticoid (GC) concentrations, and GC resistance of target cells do not represent reliable discriminatory biomarkers for chronic stress. To address this, we collected multivariate biological data from male mice exposed either to the preclinically validated chronic subordinate colony housing (CSC) paradigm or to single-housed control (SHC) condition. We then used principal component analysis (PCA), top scoring pairs (tsp) and support vector machines (SVM) analyses to identify markers that discriminate between chronically stressed and non-stressed mice. PCA segregated stressed and non-stressed mice, with high loading for some of Selye’s stress triad parameters. The tsp analysis, a simple and highly interpretable statistical approach, identified left adrenal weight and relative thymus weight as the pair with the highest discrimination score and prediction accuracy validated by a blinded dataset (92% p-value < 0.0001; SVM model = 83% accuracy and p-value < 0.0001). This finding clearly shows that simultaneous consideration of these two parameters can be used as a reliable biomarker of chronic stress status. Furthermore, our analysis highlights that the tsp approach is a very powerful method whose application extends beyond what has previously been reported.

Survival and reproductive costs of repeated acute glucocorticoid elevations in a captive, wild animal

Organisms are continuously encountering both predictable and unpredictable ecological stressors within their environment. The activation of the hypothalamic-pituitaryadrenal (stress) axis is a fundamental process allowing animals to cope with and respond to such encounters. A main consequence of HPA axis activation is the release of glucocorticoid hormones. Although short-term glucocorticoid elevations lead to changes in physiological and behavioral processes that are often adaptive, our understanding of fitness consequences of repeated acute elevations in glucocorticoid hormones over a longer time period is largely lacking. This is of particular current importance as animals are facing a significant increase in exposure to stressors including those associated with human-induced rapid environmental change. Here, we test fitness-relevant consequences of repeated exposure to glucocorticoids in the absence of natural challenges, by treating wild-caught gravid female eastern fence lizards (Sceloporus undulatus) with a daily transdermal dose of a glucocorticoid hormone until laying. This treatment causes an increase in plasma glucocorticoids that mimics the natural response lizards have when they encounter a stressor in the wild, without confounding effects associated with the encounter itself. This treatment reduced females’ reproductive success (hatching success) and survival. Further, glucocorticoid-induced reductions in reproductive success were greater when females had experienced higher temperatures the previous winter. This demonstrates the potential significant consequences of repeated exposure to acute elevations in glucocorticoid hormones. Additionally, the costs of repeated glucocorticoid elevation may be further exaggerated by an individual’s previous experience, such as the potential compounding effects of winter warming increasing animals’ vulnerability to increased glucocorticoid levels during spring breeding.

Dehydration enhances multiple physiological defense mechanisms in a desert lizard, Heloderma suspectum.

The physiological challenges associated with dehydration can induce an increase in plasma glucocorticoid concentrations, a response thought to provide the mechanism for dehydration suppressing immune function. However, a comprehensive examination of the inter-relationship of dehydration, stress and immune function has not been conducted within a single species. We previously demonstrated that Gila monsters (Heloderma suspectum), which inhabit a xeric environment with a predictable seasonal drought, have enhanced measures of innate immunity when dehydrated. These results suggest that, in this species, dehydration may not induce a glucocorticoid response, but, instead, enhances physiological defense mechanisms. To explore this possibility, we examined multiple measures of innate immunity as well as initial and reactive plasma concentrations of glucocorticoids in captive and free-ranging Gila monsters at various hydration states. Our results show that, in this species, dehydration alone does not cause a substantial increase in plasma glucocorticoids, and we provide broader evidence that dehydration enhances defensive mechanisms including stress reactivity and various measures of innate immune function. These findings suggest that physiological responses to dehydration may depend heavily on an organism's ecology. More research on the effects of dehydration on the glucocorticoid response and immunity will help clarify the interactive roles they play in response to hydration challenges and whether adaptations to water-limited environments influence these interactions.

Effects of Corticosterone on Locomotory Activity in Red-Legged Salamanders

Abstract: In amphibians, as in other vertebrates, exposure to stressors triggers an increase in plasma glucocorticoids. Glucocorticoids are believed to mediate behavioral transitions critical to coping with stressors. A common amphibian behavioral response to a variety of different stressors is inactivity. With a series of experiments, we tested the hypothesis that stress-induced decreases in locomotory activity are mediated by the glucocorticoid hormone, corticosterone (CORT). With the use of a plethodontid salamander (Red-legged Salamander, Plethodon shermani), we demonstrated that handling, a stressor, resulted in decreased locomotory activity. Next, subjects were treated with a dermal patch containing either oil vehicle or CORT. The amount of CORT used was chosen to elevate plasma CORT acutely to physiologically relevant levels relative to treatment with oil patches. Activity was measured in response to different amounts of CORT, at different times after CORT exposure, and in the presence of different...

Acute stressors increase plasma corticosterone and decrease locomotor activity in a terrestrial salamander ( Desmognathus ochrophaeus)

Vertebrates respond to the onset of an acute stressor with an acute increase in plasma glucocorticoids. The increase in plasma glucocorticoids is believed to be adaptive, helping an animal cope until the stressful episode subsides. Although much is known about the effects of chronic elevation of glucocorticoids, far less is known about the role of acute increases in glucocorticoids in mediating stress responses. To better understand the regulation and function of acute increases in plasma glucocorticoids, we measured stress-induced increases in plasma corticosterone (CORT) and the effects of stressors and exogenous CORT on activity in male Allegheny dusky salamanders ( Desmognathus ochrophaeus). Capture and handling of field-caught salamanders resulted in an acute elevation of plasma CORT during the nonmating season but not during the mating season. In laboratory-housed salamanders, a handling stressor that simulated capture resulted in decreased locomotor activity. Noninvasive elevation of plasma CORT via dermal patches did not replicate the handling-induced decrease in activity. Together, this work indicated that 1) the CORT response to the acute stressor of capture and handling was seasonally variable, 2) handling induced a decrease in locomotor activity in the laboratory, and 3) acute increases in plasma CORT did not contribute to stress-induced changes in locomotor activity. Future studies using noninvasive methods to elevate plasma CORT should illuminate the role of acute increases in plasma glucocorticoids in coordinating organismal responses to acute stressors.

Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders

Cognitive deficits are a common feature of major depression (MD), with largely unknown biological underpinnings. In addition to the affective and cognitive symptoms of MD, a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is commonly observed in these patients. Increased plasma glucocorticoid levels are known to render the hippocampus susceptible to neuronal damage. This structure is important for learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. In order to further elucidate how altered stress responsiveness may contribute to the etiology of MD, three mouse lines with high (HR), intermediate (IR), or low (LR) stress reactivity were generated by selective breeding. The aim of the present study was to investigate whether increased stress reactivity is associated with deficits in hippocampus-dependent memory tests. To this end, we subjected mice from the HR, IR, and LR breeding lines to tests of recognition memory, spatial memory, and depression-like behavior. In addition, measurements of brain-derived neurotrophic factor (BDNF) in the hippocampus and plasma of these animals were conducted. Our results demonstrate that HR mice exhibit hippocampus-dependent memory deficits along with decreased hippocampal, but not plasma, BDNF levels. Thus, the stress reactivity mouse lines are a promising animal model of the cognitive deficits in MD with the unique feature of a genetic predisposition for an altered HPA axis reactivity, which provides the opportunity to explore the progression of the symptoms of MD, predisposing genetic factors as well as new treatment strategies.

Mineralo- and Glucocorticoid Receptor mRNAs Are Differently Regulated by Corticosterone in the Rat Hippocampus and Anterior Pituitary

In most cell lines and animal tissues, glucocorticoid receptors undergo downregulation after exposure to corticosterone. However, corticosterone treatment has not shown a consistent effect on mineralocorticoid (MR) and glucocorticoid receptors (GR) in the hippocampus, and it has been rarely assessed in the anterior pituitary. In this study we investigated dose-dependent effects of corticosterone on MR and GR mRNAs in the hippocampus and anterior pituitary. Adrenalectomized rats substituted with corticosterone in drinking fluid were injected subcutaneously with vehicle or 1, 10, 50, 100, or 200 mg of corticosterone, and sacrificed 4 h later. In the hippocampus we found a progressive decrease in MR and GR mRNAs with increasing doses of corticosterone. This was significant with 50 and 100 mg corticosterone for MR mRNA and with 10–200 mg corticosterone for GR mRNA at plasma corticosterone levels above 30 µg/dl. The anterior pituitary did not show significant changes at any dose. A time-course with 2 mg of corticosterone (non-response dose range at 4 h) revealed a significant decrease in MR and GR mRNAs in the hippocampus 8 h after the subcutaneous injection. In the anterior pituitary both mRNAs showed an increase that was significant 24 h after injection for MR and from 8 to 24 h for GR. In the hippocampus, adrenalectomy (absence of corticosterone) induced a significant increase in MR and GR mRNAs on day 3, but not on days 1, 8 and 21 after adrenalectomy. In the anterior pituitary there were no significant changes at any time after adrenalectomy. In summary, we have found an in vivo corticosterone dose- and time-dependent downregulation of MR and GR mRNAs in the hippocampus, whereas anterior pituitary MRs and GRs seem relatively insensitive to the excess or the absence of corticosterone, suggesting the lack of an autoregulatory effect in this tissue. Significant mRNA changes appearing later in time could suggest a secondary response via a glucocorticoid-induced gene product. Corticosteroid receptor downregulation in the hippocampus could prevent overstimulation or tissue damage when plasma corticosterone is high, while increased corticosteroid receptors in the anterior pituitary could buffer the excessive brain drive on the pituitary during chronic stress or pathological conditions associated with increased plasma glucocorticoids, such as depression.

Social instability in female rats: effects on anxiety and buspirone efficacy.

Buspirone produces inconsistent effects in laboratory rodents. Individual housing increases the efficacy of buspirone in male rats, suggesting that the effects of this (and other) compounds become conspicuous in animals showing anxiety-like states. The effect of individual housing was, however, weak, and evident only when the locomotor suppressive effects of buspirone dissipated (i.e. 4 h after treatment). The effects of social instability, a recently developed model of social stress in female rats, was investigated on both anxiety and the anxiolytic efficacy of buspirone. Female rats were exposed to alternate days of isolation and moderate crowding for 2 weeks. Group composition was changed for each crowding phase. Basal anxiety and the anxiolytic efficacy of buspirone were assessed by the social interaction test of anxiety 24 h after the last crowding phase. Crowding appeared stressful, as it increased plasma glucocorticoid levels in less than 1 h. Anxiety-like behaviours were increased by social instability compared with stable group housing. In group housed controls, buspirone markedly suppressed locomotion, without clear effects on anxiety-related behaviours. Social instability attenuated the locomotor suppressive effects of buspirone, but made the anxiolytic effects of the compound more conspicuous. The effects of individual housing (assessed earlier) and social instability (assessed here) on buspirone efficacy appear qualitatively different. Buspirone abolishes stress-induced anxiety, but has no anxiolytic effects in controls. This is consistent with clinical findings, as the drug decreases anxiety in anxious patients but not in healthy humans. Laboratory models involving stress-induced anxiety-like states can improve our understanding of drug effects and efficacy.

Differential effects of chronic escapable versus inescapable stress on male syrian hamster ( Mesocricetus auratus) reproductive behavior

Stress decreases sexual activity, but it is uncertain which aspects of stress are detrimental to reproduction. This study used an escapable/inescapable stress paradigm to attempt to dissociate physical from psychological components of stress, and assess each component’s impact on reproductive behavior in the male Syrian hamster ( Mesocricetus auratus). Two experiments were completed using this protocol where two animals receive the same physical stressor (an electric footshock) but differ in the psychological aspect of control. One group (executive) could terminate the shock for themselves as well as a second group (yoked) by pressing a bar. Experiment 1 demonstrated a significant increase in plasma glucocorticoids at the end of a single 90-min stress session with no difference in glucocorticoid levels between the executive and yoked groups at any time point. Experiment 2 quantified male reproductive behavior prior to and immediately following 12 days of escapable or inescapable stress in executive, yoked, and no-stress control hamsters ( n = 12/group). Repeated-measures analysis of variance revealed a number of significant changes in reproductive behavior before and after stress in the three treatment groups. The most striking difference was a decrease in hit rate observed only in the animals that could not control their stress (yoked group). Hit rate in the executive males that received the exact same physical stressor but could terminate the shock by pressing a bar was nearly identical to control animals that never received any foot shock. Therefore, we conclude that coping or control can ameliorate the negative effects of stress on male reproductive behavior.

Role of Ca2+ in corticosterone‐induced muscle growth retardation

ABSTRACTThe increased plasma glucocorticoid concentration in stressful conditions stimulates muscle protein degradation, and results in growth retardation in animals. However, the mechanism is still to be clarified. The present study was undertaken to examine the participation of Ca2+ in the glucocorticoid action, using nifedipine (NIF), a Ca2+ channel antagonist. The effects of NIF on growth, differentiation, and protein degradation were examined in glucocorticoid‐treated primary cultured chick muscle cells. Muscle cell growth and cell differentiation were assessed by protein content and creatine kinase (CK) activity, respectively, and the rate of myofiblillar protein degradation was estimated by the release of Nτ‐methylhistidine (MeHis). Creatine kinase activity was increased by corticosterone (CTC) and this effect was minimized by NIF. Protein content was decreased by CTC and normalized by NIF. Nτ‐methylhistidine release was significantly increased by CTC and tended to be minimized by NIF. The present results indicate that CTC increases skeletal muscle proteolysis followed by muscle growth retardation partially because of enhanced Ca2+ influx through the NIF‐sensitive Ca2+ channel. Enhanced muscle differentiation by CTC is mediated also by the NIF‐sensitive Ca2+ channel.

Adrenal Splanchnic Innervation Modulates Adrenal Cortical Responses to Dehydration Stress in Rats

Classically, the production of glucocorticoids by the adrenal gland is thought to be controlled exclusively by adrenocorticotropic hormone (ACTH). However, there are several examples in stressed humans and animals of increased plasma glucocorticoids in the absence of increased plasma ACTH, suggesting that an additional, non-ACTH mechanism(s) may contribute to the control of glucocorticoid production. The present studies were designed to determine the role of the thoracic splanchnic nerve in controlling plasma corticosterone levels in response to chronic water deprivation in rats, a model previously reported to demonstrate dissociations between plasma corticosterone and ACTH. Briefly, rats underwent right unilateral adrenalectomy and left thoracic splanchnic nerve transection or sham transection. After recovery, rats were water deprived for 48 h or given free access to water, and then sacrificed for collection of plasma and adrenal glands. Water deprivation resulted in consistent, robust increases in plasma corticosterone that were attenuated by splanchnic nerve transection, in the absence of changes in post-dehydration plasma ACTH. Adrenal content of steroidogenic acute regulatory factor (StAR) and cyclic AMP (cAMP) were increased after dehydration; splanchnic nerve transection decreased post-dehydration adrenal cAMP, but not StAR. Splanchnic nerve transection also attenuated plasma corticosterone responses to submaximal doses of ACTH in dexamethasone-blocked, dehydrated rats, suggesting a decreased adrenal sensitivity to ACTH. Collectively, the present results demonstrate that the thoracic splanchnic nerve normally augments the adrenal corticosterone response to dehydration stress by increasing adrenal sensitivity to ACTH, and this augmentation is associated with elevations in adrenal cAMP content. These data support the hypothesis that the splanchnic innervation of the adrenal gland represents an additional physiological mechanism to control stress-induced adrenal cortical responses in vivo.

Handling during Pregnancy in the Blue Fox (Alopex lagopus): The Influence on the Fetal Pituitary–Adrenal Axis

Previous studies revealed that handling is a stressor for farmed blue foxes. The present study was designed to examine the effects of a 1-min daily handling stress applied to pregnant blue fox vixens on the function of the fetal pituitary–adrenal system. Plasma concentrations of adrenocorticotropin hormone (ACTH), cortisol, and progesterone, adrenal content of cortisol and progesterone, in vitro adrenal production of these steroids and response to ACTH, and adrenal weights were measured in control (C; n = 73) and stressed (S; n = 58) fetuses. The ACTH levels were lower in stressed fetuses than in the controls (C: males, 128.6 ± 6.1 pg/ml; females, 165.9 ± 6.1 pg/ml; S: males, 122.3 ± 5.4 pg/ml; females, 145.0 ± 8.1 pg/ml; P < 0.05). In contrast, increased plasma cortisol concentrations in both sexes were demonstrated in stressed compared with control fetuses (C: males, 9.2 ± 0.4 ng/ml; females, 9.2 ± 0.4 ng/ml; S: males, 11.8 ± 0.7 ng/ml; females, 13.2 ± 0.7 ng/ml; P < 0.00001). The same difference was observed in plasma progesterone concentrations (C: males, 1.54 ± 0.07 ng/ml; females, 1.49 ± 0.10 ng/ml; S: males, 1.86 ± 0.11 ng/ml; females, 1.74 ± 0.10 ng/ml; P < 0.01). Prenatal stress did not change the baseline adrenal production of cortisol but prevented the cortisol response to ACTH in female fetuses and decreased the progesterone production in both sexes. Additionally, prenatally stressed fetuses of both sexes had significantly lower adrenal weights than controls (C: males, 9.4 ± 0.3 mg; females, 9.5 ± 0.4 mg; S: males, 8.1 ± 0.3 mg; females, 8.2 ± 0.4 mg; P < 0.001). These results indicate that prenatal handling stress induces a dysregulation of the pituitary–adrenal axis in the fetus and suggest that increased plasma glucocorticoids in the stressed dam can cross the placenta and influence the fetal hypothalamic–pituitary–adrenal axis.

Endogenous corticosteroids modulate Clostridium difficile toxin A-induced enteritis in rats.

We examined the role of glucocorticoids in acute inflammatory diarrhea mediated by Clostridium difficile toxin A. Toxin A (5 microg) or buffer was injected in rat ileal loops, and intestinal responses were measured after 30 min to 4 h. Ileal toxin A administration increased plasma glucocorticoids after 1 h, at which time the toxin-stimulated secretion was not significant. Administration of the glucocorticoid analog dexamethasone inhibited toxin A-induced intestinal secretion and inflammation and downregulated toxin A-mediated increase of macrophage inflammatory protein-2. Adrenalectomy followed by replacement with glucocorticoids at various doses suggested that intestinal responses to toxin A were related to circulating levels of glucocorticoids. Administration of the glucocorticoid receptor antagonist RU-486 enhanced toxin A-mediated intestinal secretion and inflammation. We conclude that C. difficile toxin A causes increased secretion of endogenous glucocorticoids, which diminish the intestinal secretory and inflammatory effects of toxin A.

Dexamethasone counteracts the effect of prolactin on islet function: implications for islet regulation in late pregnancy.

Islets undergo a number of up-regulatory changes to meet the increased demand for insulin during pregnancy, including increased insulin secretion and beta-cell proliferation. It has been shown that elevated lactogenic hormone is directly responsible for these changes, which occur in a phasic pattern, peaking on day 15 of pregnancy and returning to control levels by day 20 (term). As placental lactogen levels remain elevated through late gestation, it was of interest to determine whether glucocorticoids (which increase during late gestation) could counteract the effects of lactogens on insulin secretion, beta-cell proliferation, and apoptosis. We found that insulin secretion measured over 24 h in culture and acute secretion measured over 1 h in response to high glucose were increased at least 2-fold by PRL treatment after 6 days in culture. Dexamethasone (DEX) treatment had a significant inhibitory effect on secretion in a dose-dependent manner at concentrations greater than 1 nM. At 100 nM, a concentration equivalent to the plasma corticosteroid level during late pregnancy, DEX inhibited secretion to below control levels. The addition of DEX (>1 nM) inhibited secretion from PRL-treated islets to levels similar to those produced by DEX treatment alone. Bromodeoxyuridine (10 microM) staining for the final 24 h of a 6-day culture showed that PRL treatment increased cell proliferation 6-fold over the control level. DEX treatment alone (1-1000 nM) did not reduce cell division below the control level, but significantly inhibited the rate of division in PRL-treated islets. YoYo-1, an ultrasensitive fluorescent nucleic acid stain, was added (1 microM; 8 h) to the medium after 1-3 days of culture to examine cell death. Islets examined under confocal microscopy showed that DEX treatment (100 nM) increased the number of cells with apoptotic nuclear morphologies. This was quantified by counting the number of YoYo-labeled nuclei per islet under conventional epifluorescence microscopy. The numbers of YoYo-1-positive nuclei per islet in control and PRL-treated islets were not different after 3 days of culture. However, DEX treatment increased YoYo-1 labeling 7-fold over that in controls. DEX also increased YoYo-1 labeling in PRL-treated islets 3-fold over the control level. These data show that the increased plasma glucocorticoid levels found during the late stages of pregnancy could effectively reverse PRL-induced up-regulation of islet function by inhibiting insulin secretion and cell proliferation while increasing apoptosis.

Corticotropin-releasing Factor and Adrenocorticotrophic Hormone as Potential Central Mediators of OB Effects

OB (leptin) has been identified as a factor that suppresses appetite and stimulates metabolism. Attention has focused on the hypothalamus as its potential site of action, but OB could also act on other brain regions. In addition, the paradox of high OB levels in obese humans remains unresolved. Here we show in mice that both the long and short form of the OB receptor are expressed not only in the hypothalamus but also in the amygdala and pituitary. Recombinant murine OB elicited the release of corticotropin-releasing factor from superfused brain slice preparations containing hypothalamus or amygdala. Because corticotropin-releasing factor inhibits appetite and stimulates metabolism, it may be a key mediator of central OB effects. Recombinant OB also induced pituitary release of adrenocorticotrophic hormone. Because adrenocorticotrophic hormone-induced elevation of plasma glucocorticoid levels can inhibit corticotropin-releasing factor release via negative feedback, the OB effects on pituitary adrenocorticotrophic hormone release may be pertinent to human obesity, which combines increased plasma glucocorticoid levels with elevated levels of OB. An imbalance between the effects of OB on corticotropin-releasing factor release from the hypothalamus and on adrenocorticotrophic hormone release from the pituitary could contribute to obesity.

Intra-abdominal sepsis: an immunocytochemical study of the small intestine mucosa.

AIM: To investigate immunocytochemical changes in intestinal tissues from patients with intra-abdominal sepsis, and to relate the changes to the possibility of enhanced bacterial adhesion and translocation. METHODS: Tissues from...

Stress and the immune system in the etiology of anxiety and depression

There is clinical and experimental evidence that various aspects of the immune and endocrine systems are severely compromised in chronic stress and depression. For example, it has been shown that a reduced lymphocyte response occurs to mitogens in depressed patients, effects that are not reversed by chronic antidepressant treatment. By contrast, monocyte phagocytosis is increased, while neutrophil phagocytosis is decreased in depressed patients. Such changes are normalized by effective antidepressant treatment. The results of such studies and others that demonstrate alterations in noncellular immune processed in depression indicate that the changes in immune function correlate with the severity and duration of the external and/or internal stressful stimuli. There is evidence that some of the immune changes are a reflection of increased plasma glucocorticoids that characterize both stress and depression. However, it is also apparent that the cytokines, prostaglandins, and corticotrophic releasing factor (CRF) also play an important role in initiating the behavioral and pathophysiological changes that are characteristic of both depression and chronic stress. This review attempts to critically assess the interplay between CRF, the immune and neurotransmitter systems, and behavior in chronic stress and depression.

ACTH does not control neonatal seizures induced by administration of exogenous corticotropin-releasing hormone.

ACTH has been used extensively for treatment of massive infantile spasms (MIS) and other intractable seizures. The mechanisms by which ACTH exerts anticonvulsant effects are unknown. ACTH is a neuropeptide with both endocrine and neuromodulatory properties; its efficacy against MIS could derive from intrinsic anticonvulsant properties or from hormonal effects, either directly or through glucocorticoids. We tested ACTH activity against exogenous corticotropin-releasing hormone (CRH)-induced seizures in the infant rat model. CRH was administered into the cerebral ventricles of 85 infant rats aged 5-13 days. ACTH was used either 20-60 min before CRH administration or "chronically" (pretreatment with four doses of ACTH every 6 h, before CRH administration). In a separate group of rat pups, we measured plasma corticosterone to ascertain ACTH availability. Administration of CRH, an age-specific endogenous convulsant, resulted in a prolonged series of seizures after 2- to 55-min latency. There was no difference in latency between controls (9.5 +/- 1.2 min) and ACTH-treated rats (12.4 +/- 2.8 min for combined acute and chronic groups). CRH-induced seizure duration (88.2 +/- 9 vs. 74.7 +/- 9.4 min) and severity of seizures was also unchanged by ACTH treatment. ACTH reached the circulation and caused significant increase in plasma glucocorticoids. ACTH does not block the convulsant action of exogenous CRH in infant rats. An alternative mechanism for the anticonvulsant effect of ACTH may be suppression of synthesis and secretion of an endogenous convulsant, i.e., CRH.