Exposure to forced swim stress does not alter central production of IL-1

In recent years, there has been increasing recognition that pro-inflammatory cytokines play a role in behavioral and physiological alterations produced by exposure to psychological stressors. Indeed, increases in central IL-1 production have been observed following stressors such as inescapable tailshock and social isolation, while no changes in IL-1 have been observed following other stressors (e.g., exposure to a predator). The goal of the following work was to establish whether exposure to the forced swim test (FST), a commonly used animal model of behavioral despair/depression, leads to an increase in central or peripheral production of IL-1. Briefly, adult male Sprague-Dawley rats (n=8 per group) were forced to swim for 15-30 min (25 degrees C) and killed at various intervals (ranging from immediately to 24 h) following stressor termination. Brains (hippocampus, hypothalamus, posterior cortex) and multiple peripheral tissues (pituitary, adrenals, spleen, plasma) were then dissected and frozen for subsequent measurement of IL-1 using a commercially available enzyme-linked immunosorbent assay. No observable increases in IL-1 were found in rats that were forced to swim acutely, or in rats that were re-exposed to the forced swim stressor 24 h later. These data suggest that exposure to forced swim does not lead to an increase in central production of IL-1, suggesting that the central IL-1 system is unlikely to play a role in mediating behavioral consequences of this stressor. However, these data do not exclude the possibility that other pro-inflammatory cytokines (such as IL-6 and TNF-alpha) might be produced in response to forced swim exposure.     

Prenatal stress in rats predicts immobility behavior in the forced swim test. Effects of a chronic treatment with tianeptine

Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment.     

Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat

The Wistar Kyoto (WKY) rat may be a useful model for the study of depressive behavior because they exhibit exaggerated responses to a number of stressors. These studies compared the behavioral and endocrine responses to swimming stress in WKY rats with Sprague-Dawley (SD) rats. In the first experiment, the onset of behavioral immobility and the endocrine stress responses (adrenocorticotropin hormone (ACTH) and corticosterone (CORT)) were examined as the duration of a swimming session was increased. In the second experiment, WKY and SD rats were swum for 15 min, then sacrificed at different intervals after completion of the swim, to examine the time course of endocrine stress responses. The final experiment compared the suppression of ACTH and CORT secretion by dexamethasone of peak diurnal ACTH and CORT levels in WKY and SD rats. Behaviorally, the WKY rats displayed early and prolonged immobility compared to SD rats regardless of the length of the swim stress. Plasma CORT and ACTH increased in WKY and SD rats as the duration of the stressor lengthened. The swim stress (15 min) produced higher levels of ACTH and CORT secretion at the end of the stress interval that persisted after termination of the stressor in WKY compared to SD rats. Peak diurnal CORT levels, but not ACTH levels, were higher in WKY than in SD rats. Dexamethasone suppressed ACTH levels less in WKY than in SD rats. These results indicate that the WKY rat that displays increased behavioral immobility also demonstrates exaggerated secretion of stress hormones during swimming stress, and the results may be due, in part, to reduced sensitivity of glucocorticoid receptors that supply negative feedback to the hypothalamic-pituitary-adrenal axis. The exaggerated behavioral and endocrine stress responses in the WKY rat support its potential usefulness as a model for studying stress-evoked depressive behavior.     

Comparison of neuroendocrine and behavioral effects of ipsapirone, a 5-HT1A agonist, in three stress paradigms: immobilization, forced swim and conditioned fear.

Ipsapirone is an anxiolytic drug and a serotonin_1A (5-HT_1A) agonist. The aim of the present study was to investigate the effects of low doses of ipsapirone on the hormonal and behavioral response to three stress procedures: immobilization, forced swim and conditioned emotional response (CER). We examined the effect of ipsapirone (0.1, 0.5 or 1.0 mg/kg) on plasma renin concentration (PRC), adrenal corticotropic hormone (ACTH), corticosterone, prolactin and defacation in rats exposed to immobilization, forced swim or CER stress. All three stressors significantly elevated all the hormone levels (P < 0.01). Immobilization-induced elevations of PRC, and corticosterone were inhibited by the highest doses of ipsapirone (0.5 and 1 mg/kg, i.p.). However, ipsapirone did not modify the immobilization-induced elevations of plasma ACTH, prolactin or defecation. Ipsapirone was relatively ineffective at reducing the endocrine responses to forced swim. Ipsapirone reduced some, but not all of the hormonal responses to CER stress. CER-induced elevations of corticosterone and prolactin were not inhibited by ipsapirone. However, the ACTH response to CER was significantly (P < 0.01) inhibited by all doses of ipsapirone and the highest dose of ipsapirone attenuated the renin response. In contrast with the hormonal responses, ipsapirone inhibited all of the behavioral responses to CER stress. Ipsapirone inhibited CER-induced freezing behavior and defecation, while dose-dependently reversing the suppressive effect of CER on exploring, grooming and rearing behaviors. In conclusion, there is a dissociation between the influence of ipsapirone on the endocrine and behavioral responses to CER stress. Ipsapirone also has differential effects on the neuroendocrine response to the three stressors studied. Ipsapirone was most effective in attenuating the hormonal responses to CER, followed by immobilization and swim stress. Of the hormones studied, the stimulation of renin secretion after exposure to the three stressors was most sensitive to ipsapirone, while corticosterone and prolactin were the least sensitive to ipsapirone.     

Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress

Our previous research indicates that the extracellular signal-regulated kinase (ERK)-cyclic AMP-responsive-element-binding protein (CREB) signal system may be involved in the molecular mechanism of depression. The present study further investigated the effect of antidepressant fluoxetine on the ERK-CREB signal system and the depressive-like behaviors in rats. Fluoxetine was administrated to either naive rats or stressed rats for 21 days. The results showed that chronic forced swim stress induced depressive-like behaviors and decreased the levels of P-ERK2, P-CREB, ERK1/2 and CREB in hippocampus and prefrontal cortex. Fluoxetine alleviated the depressive-like behaviors and reversed the disruptions of the P-ERK2 and P-CREB in stressed rats. Fluoxetine also exerted mood-elevating effect and increased the levels of the P-ERK2 and P-CREB in naive rats. These results suggest that the ERK-CREB signal system may be the targets of the antidepressant action of fluoxetine and participate in the neuronal mechanism of depression.     

Effects of a chronic inflammatory stress on levels of pro-opiomelanocortin-derived peptides in the rat spleen and thymus

Adjuvant-induced arthritis (AA) in specific strains of rats is an immunologically mediated inflammatory disease which is also characterised by activation of the endocrine system. To further investigate the effects of AA on processing of the pro-opiomelanocortin (POMC) precursor in rat immune tissues, we utilised radioimmunoassays for adrenocorticotropin (ACTH), β-endorphin and α-melanocyte-stimulating hormone (α-MSH) to measure these peptides in the spleen and thymus. 14 days following adjuvant injection, spleen levels of ACTH were elevated in the AA group (4.47 ± 1.04 ng/g tissue, n = 9) compared to controls 2.42±0.4 ng/g) and exacerbation of the disease by removal of circulating glucocorticoids through bilateral adrenalectomy (ADX) resulted in further elevation of spleen ACTH (5.11 ± 1.22 ng/g). β-Endorphin levels in both the AA (10.60 ± 1.61 ng/g) and AA/ADX (13.37 ± 2.36 ng/g) groups were higher than controls 5.57 ± 0.65 ng/g). Conversely, α-MSH spleen levels were decreased in the AA (2.89 ± 0.22 ng/g) and AA/ADX (2.22 ± 0.33 ng/g) groups compared to controls (4.62 ± 0.45 ng/g) and were also decreased following adrenalectomy. In the thymus, ACTH levels were elevated in the AA group (8.95 ± 1.41 ng/g) compared to controls (5.79 ± 0.63 ng/g), and the same pattern wasevident for thymic α-MSH (0.64 ± 0.08 ng/g in AA animals compared to control levels of 0.35 ± 0.03 ng/g). Following G50 gel filtration, ACTH and β-endorphin immunoreactivities (ir) were present in both spleen and thymus as two peaks, one which eluted near the void volume and one which eluted in a lower molecular mass position than the standards. However, ir-ACTH and ir-β-endorphin were present in multiple peaks in AA spleen extracts, indicating extensive processing. These data are the first evidence that ir-ACTH and ir-β-endorphin tissue content and POMC processing in the spleen and thymus can be influenced by a chronic stress.     

Repeated swim stress increases pain-induced expression of c-Fos in the rat lumbar cord

We have previously demonstrated that repeated swim stress produces a long-lasting cutaneous hyperalgesia in rats. We have now looked at c-Fos expression in the spinal lumbar cord of male Sprague-Dawley rats subjected to 10-20 min daily sessions of forced swimming for 3 consecutive days. Control rats were subjected to sham swimming or were completely naive. Forty-eight hours later, nociception was assessed by recording for 90 min the nociceptive behavior evoked the injection of 1% formalin in the hind paw. Thirty min later, the rats' spinal cords were removed for c-Fos immunocytochemistry. Total pain scores were 45% higher in swim stressed rats compared to control animals due an increased nociceptive behavior during last 70 min of the recording period. In addition, the number of c-Fos-immunoreactive nuclei was 40% higher in the lumbar ipsilateral dorsal horn (L4-L5) of swim stressed rats than in controls, being the highest relative increase, relative to the control groups, observed in laminae III-IV, followed by laminae V-VI, with the smallest difference in laminae I-II. c-Fos expression in the contralateral dorsal horn was higher in swim stressed rats than in sham and nai;ve rats. In the absence of a nociceptive stimulus, a low level of c-Fos expression was observed mainly in laminae I, II, V, and VI, being higher in swim stressed rats than in sham rats. These findings suggest that repeated inescapable and uncontrollable stress could induce a sensitization and activation of sensory neurons at the spinal level.     

Contents of corticotropin-releasing hormone and arginine vasopressin immunoreactivity in the spleen and thymus during a chronic inflammatory stress

We have previously found that proopiomelanocortin (POMC) mRNA and levels of adrenocorticotropin (ACTH) and β-endorphin peptides are increased in the spleen and thymus of rats with adjuvant-induced arthritis (AA), an immunologically mediated inflammatory disease. To determine whether alterations in immune tissue POMC during AA are also accompanied by changes in immune tissue corticotropin-releasing hormone immunoreactivity (ir-CRH) and arginine vasopressin (AVP), we measured ir-CRH and AVP by radioimmunoassays in spleen and thymic extracts 14 days following injection of adjuvant. Ir-CRH was detectable in all extracts of spleen and thymus. Total contents of ir-CRH in the spleen and thymus were not altered following arthritis, although a significant decrease was observed in splenic extracts from arthritic rats (40.0 ± 4.2 fmol/g tissue) compared to controls (69.5 ± 8.4 fmol/g tissue) when contents were expressed as amount per weight of tissue. Low levels of AVP were also detected in immune tissues, with contents significantly increased in spleens from arthritic animals (17.4 ± 1.6 fmol/g tissue) compared to controls (10.6 ± 1.9 fmol/g) but thymic contents of AVP were not altered by arthritis (10.6 ± 1.3 fmol/g) compared to controls (9.2 ± 0.7 fmol/g). Control levels of AVP were significantly higher in spleens and thymuses from female rats (53 ± 5 and 25 ± 4 fmol/g tissue, respectively) compared to males. G-50 chromatography revealed that the principal form of splenic ir-CRH is CRH(1–41), although in non-arthritic animals some ir-CRH eluted in a position indicating a slightly larger form. Therefore the responses of ir-CRH contents in tissues of the immune system differ from those observed for POMC mRNA and POMC peptide products during this chronic inflammatory stress.     

Gender differences of acute and chronic administration of dehydroepiandrosterone in rats submitted to the forced swimming test

Previous pre-clinical and clinical studies investigating the antidepressant potential of DHEA revealed conflicting results. In this study, the effects of exogenous DHEA on performance in the forced swimming test (FST) were examined in male and female Wistar rats in different phases of the estrous cycle. Furthermore, the effects of treatment and of the FST, on corticosterone and DHEA serum levels were investigated. Acute administration of DHEA (2 mg/kg) significantly increased freezing only in proestrus female rats. Similarly, the chronic administration of DHEA (2 mg/kg) increased freezing duration and decreased climbing behavior but only in females in diestrus II compared to those given vehicle. These results demonstrate that chronically administered DHEA induces a depressant-like effect, and this effect is sex dependent. There was no direct correlation between corticosterone levels or the corticosterone/DHEA ratio and the behaviors studied. After the FST, serum DHEA and corticosterone levels were increased, with females showing higher DHEA levels than males. Nevertheless, corticosterone levels were unaltered with chronic procedure; an effect that was independent of sex and treatment. These findings are relevant for research examining alternative treatment for depression and may elucidate the gender differences involved in stress-related diseases.     

The afferent innervation of the thymus gland in the rat

The afferent nervous supply to the thymus gland has been investigated by means of the retrograde transport of horseradish peroxidase. It has been shown that the thymus receives an afferent supply from the nodose ganglia of the vagus and from the dorsal root ganglia C₁–C₇. The afferent innervation of the right and left thymic lobes is bilaterally organized; the fibers of a small celled population of nodose ganglion neurons cross outside the thymus and those of a larger celled population cross within the thymus gland. The functional implications of these findings are discussed in the context of central nervous system-immune system interactions.     

Stereotaxic localization of corticosterone to the amygdala enhances hypothalamo-pituitary-adrenal responses to behavioral stress

The amygdala is involved in behavioral, autonomic, and neuroendocrine responses to stressful stimuli. The goal of the current study was to determine the effect of directly elevating glucocorticoids in the amygdala on hypothalamo-pituitary-adrenocortical (HPA) responses to the elevated plus maze, a behavioral stressor known to activate the amygdala. Micropellets (30 microg) of crystalline corticosterone or cholesterol (control) were implanted bilaterally at the dorsal margin of the CeA in male Wistar rats; vascular catheters were also placed at this time. Five days post-surgery, blood samples were drawn at 07:00 and 19:00 h to assess diurnal rhythm of plasma corticosterone. At 7 days post-implantation, rats were subjected to behavioral stress using an elevated plus maze and blood was collected 15 min prior to stress, and at 15, 45, and 90 min after the initiation of the stressor. Corticotropin releasing factor (CRF) and arginine vasopressin (AVP) mRNA levels were analyzed by in situ hybridization in the medial parvocellular division of the hypothalamic paraventricular nucleus (mpPVN) in corticosterone- and cholesterol-implanted rats either not exposed to the elevated plus maze (control) or 4 h post-behavioral stress. Localization of corticosterone to the amygdala had no effect on diurnal rhythm of corticosterone secretion. Behavioral stress significantly increased peak plasma corticosterone levels in both groups to a similar level. However, in the corticosterone implanted rats, plasma corticosterone concentrations at 45 and 90 min post-stress were significantly greater compared to control rats indicating a prolonged corticosterone response to behavioral stress. In non-stressed rats, corticosterone delivery to the amygdala elevated basal CRF mRNA in the mpPVN to levels similar to those observed post-stress in control animals; no further increase was observed in CRF mRNA following stress. Behavioral stress resulted in a significant elevation in CRF mRNA in cholesterol controls. Basal AVP mRNA levels were unaffected by corticosterone implants. AVP mRNA did not increase in cholesterol implanted rats in response to behavioral stress. However, AVP mRNA levels were higher in corticosterone implanted rats post stress compared to cholesterol treated controls. In conclusion, direct administration of corticosterone to the amygdala increases plasma corticosterone in response to a behavioral stressor without altering the diurnal rhythm in plasma corticosterone. Elevated basal levels of mpPVN CRF mRNA, and the induction of a mpPVN AVP mRNA response to the behavioral stressor implicate enhanced ACTH secretagogue expression in the increased HPA response to corticosterone modulation of amygdala function.     

Unpredictable and uncontrollable stress impairs neuronal plasticity in the rat hippocampus

Almost by definition, learning and the effect of stress on learning represent modifications of existing neuronal circuitry. Under some circumstances, this modification can be measured electrophysiologically. One such measure of plasticity is long-term potentiation (LTP), a long-lasting increase in synaptic efficacy following brief exposure to tetanic stimulation. In 1987, Foy et al. reported that hippocampal LTP was impaired by exposure to inescapable shock. We have recent evidence that the impairment in LTP can be prevented by allowing the animal to learn to escape the shock (Shors et al., 1989), indicating that the stress effect is to some extent mediated by "psychological" variables. Regardless of LTP's putative role in learning and memory processes, such a stress-induced decrease in neuronal plasticity is likely to have profound effects on the behaving organism.     

Exposure to repeated low-level formaldehyde in rats increases basal corticosterone levels and enhances the corticosterone response to subsequent formaldehyde

Low-level exposure to volatile organic compounds may produce symptoms in humans reporting multiple chemical sensitivity (MCS) through altered hypothalamic–pituitary–adrenal (HPA) axis functioning. We determined whether repeated formaldehyde (Form) exposure would alter corticosterone (CORT) levels in a rat model of MCS. Male Sprague–Dawley rats were given acute chamber exposures to Air or Form (0.7 or 2.4 ppm), and trunk blood was collected 20 or 60 min later. All groups showed increased CORT levels above naïve basal levels at 20 min and a return to baseline by 60 min, with no differences between treatment groups. The second experiment examined the effect of repeated Form exposure (1 h/day×5 days/week×2 or 4 weeks) on basal CORT levels and after a final challenge. Basal CORT was increased above naïve values after 2 week exposure to Air or 0.7 ppm Form. By 4 week, CORT levels in the Air group returned to naïve values, but remained elevated in the 0.7 ppm Form group. There were no differences in basal CORT levels among either 2.4 ppm exposed groups. After a final Air or Form challenge, the 2 and 4 week Air and 0.7 ppm Form groups had elevated CORT levels similar to their acute response, while the 2 and 4 week 2.4 ppm Form groups had elevated CORT levels compared to their acute response, indicating enhanced reactivity of the HPA axis to subsequent Form. These findings suggest that altered HPA axis functioning occurs after repeated low-level Form exposure, and may have implications for mechanisms mediating MCS in humans.     

Peculiar response of adolescent mice to acute and chronic stress and to amphetamine: evidence of sex differences

Although final brain size and the number of available neurons and axons appear to be established early in infancy, plasticity of the brain continues during adolescence through an integrated process of overproduction and elimination of synapses and receptors. In addition, hormonal levels change dramatically during this period, as a result of the onset of puberty. This age-specific condition has been suggested to serve as a permissive factor for the emergence of a number of early-onset neuropsychiatric disorders, including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and perhaps substance abuse. However, relatively few investigations have focused on animal models of this developmental phase. The periadolescent rodent (similar30-45-day-old), has been proposed as a useful model. Periadolescent rats and mice are generally associated with a peculiar behavioral profile, consisting of basal hyperactivity, high attraction towards novel stimuli and a marked involvement in affiliative and playful behaviors. Moreover, a unique profile of psychopharmacological responsivity characterizes rodents around this age. Recent experiments by our group investigated age-related discontinuities in the response of the hypothalamic-pituitary-adrenal axis (HPA) to both stress and psychostimulants. The latter are often administered as therapeutic drugs to children with ADHD, which have been also associated with an impaired response to stress and abnormalities in HPA axis function. Indeed, an altered functioning of the HPA axis has been proposed as a possible risk factor and a potential marker for such a behavioral vulnerability. Animals were studied at adulthood (> pnd 70) or during periadolescence. Experiment I characterized basal corticosterone (CORT) levels in naive mice kept undisturbed in standard social conditions from weaning to sacrifice. Periadolescent male mice showed higher basal CORT levels than adult subjects, suggesting that the set up of the HPA axis is physiologically elevated during adolescence. In experiment II, we investigated age-related differences in the response to both acute and chronic stress conditions. Periadolescent and adult mice were housed either in a standard (three animals per cage) or in a crowding condition (nine animals per cage). The latter has been indeed reported to potentiate the subsequent reaction to acute stress in adult rodents. At the end of this period and following 24 h individual housing, mice were injected with either saline (SAL) or a standard amphetamine (AMPH) dose (2 mg/kg), and faced with a mild acute psychological stress, namely removal of sawdust from the home cage. Important sex differences emerged in animals of the two ages. Periadolescent females showed a reduced CORT response to acute stress. Within the adult male group, the chronic crowding condition produced a prominent potentiation of CORT response to the acute stress challenge. Conversely, this profile was not evidenced in periadolescents. These results indicate a strong role for gender and social variables in the response of periadolescent subjects to the various aspects of stress. As for AMPH effects, in the absence of significant changes in adult subjects, the drug produced a marked CORT release in periadolescent mice. A better understanding of neuroendocrine-related AMPH effects as a function of social and environmental risk factors during adolescence, might deepen our knowledge on the neurobiological bases of genetically determined neuropsichiatric disorders and possibly improve the therapeutical efficacy of psychostimulant drugs.     

Higher inherent fearfulness potentiates the effects of chronic stress in the Japanese quail

There is considerable variability in the susceptibility of individuals to the adverse effects of chronic stress. In humans and other mammals, individual traits such as high anxiety are proposed as a vulnerability factor for the development of stress-related disorders. In the present study, we tested whether a similar behavioural trait in birds, higher emotional reactivity, also favours the occurrence of chronic stress-related behavioural and physiological dysfunction.For this, lines of Japanese quail divergently selected for a typical fear response in birds, the duration of tonic immobility, were subjected to unpredictable aversive stimulation over 2 weeks. Previous studies demonstrate that the selection program modifies the general underlying emotionality of the birds rather than exerting its effect only on tonic immobility.Interestingly, only birds selected for their higher emotionality exhibited significantly enhanced latency to first step and decreased locomotor activity in the open-field test after exposure to chronic stress compared to non-stressed control birds. This effect of chronic stress was selective for the tested dimension of bird emotional reactivity because there was no observed effect on the tonic immobility response. Moreover, chronically stressed birds selected for their higher emotionality exhibited significantly decreased basal corticosterone levels, a physiological marker of stress. These findings show that chronic stress is associated with changes in emotional reactivity and related physiological markers in birds. They also highlight emotional reactivity as an important predisposing factor for the occurrence of the adverse effects of chronic stress in birds.     

Reaction of sleep–wakefulness cycle to stress is related to differences in hypothalamo–pituitary–adrenal axis reactivity in rat

Acute stress is known to modify sleep–wakefulness cycle, although with considerable interindividual differences. The origin of these individual differences remains unknown. One possibility is an involvement of the hypothalamo–pituitary–adrenal axis (HPA), as its reactivity is correlated with an individual's behavioral reactivity to stress, and it is known to influence the sleep–wakefulness cycle. The present study was designed to analyze relationships between natural differences in behavioral reactivity to stress associated with differential HPA reactivity and stress-induced changes in sleep–wakefulness. Adult rats were classified into two sub-groups according to their locomotor reactivity to a mild stress (novel environment): the `low responders (LR)' and the `high responders (HR)' animals exhibited different glucocorticoid secretion in response to stress. We show that immobilization stress induced an increase in wakefulness in LR animals and a decrease in wakefulness in HR animals. On the other hand, paradoxical sleep was increased in both LR and HR animals. Moreover, we observed that LR animals slept more than the HR animals, whereas the two groups had similar levels of paradoxical sleep. These results indicate that the response of the sleep–wakefulness cycle to stress is related to the behavioral reactivity to stress, in turn governed by the individual's reactivity of the HPA axis. The involvement of dopaminergic mechanisms is discussed.     

Corticosterone mitigates the stress response in an animal model of PTSD

Activation of glucocorticoid receptor signaling in the stress response to traumatic events has been implicated in the pathogenesis of stress-associated psychiatric disorders such as post-traumatic stress disorder (PTSD). Elevated startle response and hyperarousal are hallmarks of PTSD, and are generally considered to evince fear (DSM V). To further examine the efficacy of corticosterone in treating hyperarousal and elevated fear, the present study utilized a learned helplessness stress model in which rats are restrained and subjected to tail shock for three days. These stressed rats develop a delayed long-lasting exaggeration of the acoustic startle response (ASR) and retarded body weight growth, similar to symptoms of PTSD patients (Myers et al., 2005; Speed et al., 1989). We demonstrate that both pre-stress and post-stress administration of corticosterone (3 mg/kg/day) mitigates a subsequent exaggeration of the ASR measured 14 days after cessation of the stress protocol. Furthermore, the mitigating efficacy of pre-stress administration of corticosterone (3 mg/kg/day for three days) appeared to last significantly longer, up to 21 days after the cessation of the stress protocol, in comparison to that of post-stress administration of corticosterone. However, pre-stress administration of corticosterone at 0.3 mg/kg/day for three days did not mitigate stress-induced exaggeration of the ASR measured at both 14 and 21 days after the cessation of the stress protocol. In addition, pre-stress administration of corticosterone (3 mg/kg/day for three days) mitigates the retardation of body weight growth otherwise resulting from the stress protocol. Congruently, co-administration of the corticosterone antagonist RU486 (40 mg/kg/day for three days) with corticosterone (3 mg/kg/day) prior to stress diminished the mitigating efficacy of the exogenous corticosterone on exaggerated ASR and stress-retarded body weight. The relative efficacy of pre versus post administration of corticosterone and high versus low dose of corticosterone on stress-induced exaggeration of innate fear response and stress-retarded body weight growth indicate that exogenous corticosterone administration within an appropriate time window and dosage are efficacious in diminishing traumatic stress induced pathophysiological processes. Clinical implications associated with the efficacy of prophylactic and therapeutic corticosterone therapy for mitigating symptoms of PTSD are discussed, particularly in relation to diminishing hyperarousal and exaggerated innate fear response.     

The effects of restraint or hypertonic saline stress on corticotrophin-releasing factor, arginine vasopressin, and proenkephalin A mRNAs in the CFY, Sprague-Dawley and Wistar strains of rat

It is generally assumed that the stress response of different strains of rat will be identical following exposure to acute stress. In the present study we have examined the activation of the hypothalamo-pituitary-adrenal axis in the Wistar, Sprague-Dawley and CFY strains of rat following exposure to either the predominantly psychological stress of restraint or the physical stress of i.p. hypertonic saline injection. We have investigated the hypothalamic activation of corticotrophin-releasing factor (CRF) and proenkephalin A (PEA) mRNAs in the parvocellular cells of the paraventricular nucleus (PVN) and arginine vasopressin (AVP) in both the magnocellular and parvocellular regions in the PVN following acute stress. In addition we have measured corticosterone as an index of end-point activation. Circulating corticosterone and CRF mRNA were increased in all three strains following either stress. AVP and PEA mRNAs were increased following hypertonic saline but only in the CFY strain following restraint. Overall the relative increase in the parameters measured was greater in the CFY strain of rat than the other strains. These data demonstrate marked differences in response to acute stress in the three strains of rat examined. These varying responses must be taken into consideration when designing or interpreting any study investigating the stress response.     

Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen

This study was designed to investigate whether the pattern of hypothalamic and splenic cytokine expression induced by peripheral administration of a bacterial lipopolysaccharide (LPS) is affected by prior exposure to LPS derived from another bacterial strain. Injection of LPS from Salmonella enteritidis (LPS₂) alone resulted in increased hypothalamic gene expression of IL-1β, IL-6, TNFα, IL-1ra and IL-10. However, pre-exposure to LPS derived from Escherichia coli (LPS₁) 3 weeks before, significantly attenuated hypothalamic IL-1ra, IL-6 and IL-10 expression. IL-1β expression also tended to be lower. This pattern contrasted with the robust cytokine expression in the spleen of LPS₂-treated rats previously exposed to LPS₁, since pre-treatment with endotoxin resulted in a significantly greater response of IL-1β and IL-1ra to LPS₂. Expression of TNFα and IL-10 also tended to be higher. Pre-treatment with LPS₁ did not significantly affect the marked increase in corticosterone and adrenaline blood levels induced by LPS₂. Thus, while endotoxin pre-exposure seemed not to induce a “tolerant” state in the periphery as judged by the immune and endocrine parameters evaluated upon re-stimulation, expression of four of the six cytokines measured was decreased in the hypothalamus. This is the first demonstration that endotoxin priming can differentially affect cytokine expression in the central nervous system and peripheral tissues when a host is confronted with a second, acute, pro-inflammatory stimulus. These results may provide new evidence for the involvement of cytokine pathways in the central nervous system in modulating peripheral inflammation and mediating cognitive and behavioural alterations during inflammatory diseases.