Hypothalamo-Pituitary-Adrenocortical Regulation Following Lesions of the Central Nucleus of the Amygdala

Previous reports indicate that the central nucleus of the amygdala (CeA) stimulates adrenocorticotropin and corticosterone secretion, suggesting a role for this region in central hypothalamo-pituitary-adrenocortical (HPA) stress regulation. To evaluate this hypothesis, this study assessed the impact of CeA lesion on the response of hypophysiotrophic paraventricular nucleus (PVN) neurons to acute restraint and chronic unpredictable stress exposure. In contrast to previous reports, CeA lesions did not affect corticosterone or ACTH secretion induced by acute stress. Acute restraint increased PVN corticotropin releasing hormone (CRH) mRNA expression, increased the number of parvocellular PVN neurons expressing the co-secretagogue arginine vasopressin (AVP), and induced cFOS mRNA expression in the parvocellular PVN. However, there was no additional effect of CeA lesion on any measure of PVN activation. Chronic unpredictable stress exposure induced long-term activation of the HPA axis, noted by thymic involution, adrenal hypertrophy and increased PVN CRH mRNA expression. Stress-induced changes in thymus and adrenal weights were not affected by CeA lesion. Further, CeA lesion rats did not differ from controls in post-stress CRH mRNA expression. However, basal CRH mRNA expression was increased in the PVN of CeA rats, suggesting that the CeA plays a role in long-term inhibition of the PVN. The results of these studies are not consistent with the hypothesis that the CeA is necessary for stress-induced pituitary-adrenocortical activation. Rather, this region may play a stressor-specific modulatory role in regulation of HPA function.     

The effect of adrenalectomy on Fos expression in vasopressinergic and oxytocinergic neurons in response to stress in the rat

This study evaluated the responses of vasopressin (AVP) and oxytocin (OT) neurons to alterations in hypothalamo-pituitary axis activity by adrenalectomy (ADX) or after restraint stress compared with basal conditions. Wistar male rats were perfuse-fixed by cardiac perfusion under anesthesia 3 h, 1, 3 and 14 days after ADX or Sham surgery. Coronal hypothalamic sections were used for evaluation of Fos, AVP and OT expression by immunohistochemistry. Under basal conditions and after stress, Fos-AVP double labeling showed no difference in the magnocellular subdivisions of the paraventricular nuclei (PVN) or in the supraoptic nuclei (SON), suggesting that the magnocellular AVP system is unlikely to contribute to ACTH secretion after restraint in both Sham and ADX rats. Fos-AVP double labeling in the parvocellular medial paraventricular nucleus (PaMP) in ADX groups was increased after 3 h in basal conditions, and in all periods after restraint stress. There were no differences between Sham and ADX groups in Fos-OT double labeling in any subdivision of the PVN; however, in the SON, the number of Fos-OT double labeled cells was increased at all time-points after stress in the ADX group. Fos expression was increased in the PaMP after 3 h and after restraint stress in the Sham and ADX groups, especially in the ADX group. In conclusion, Fos expression in different cell populations of the PVN can be differentially regulated by short- and long-term absence of glucocorticoid negative feedback and also by stress-related excitatory and/or inhibitory neural inputs. The Fos-AVP double labeling findings in the PaMP also indicate a minor participation of these vasopressinergic neurons in the regulation of the HPA axis after ADX.     

Dexamethasone and stressor-magnitude regulation of stress-induced transcription of HPA axis secretagogues in the rat

Regulation of the production of hypothalamic-pituitary-adrenal (HPA) axis secretagogues, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), may be differentially sensitive to the negative feedback effects of glucocorticoids. We chose to study this phenomenon by examining the ability of dexamethasone to influence CRH and AVP heteronuclear RNA (hnRNA) levels in an escapable/inescapable (ES/IS) foot-shock stress paradigm. On Day 1, adult male rats were subjected to either ES or IS foot-shock; on Day 2, saline or dexamethasone (100 microg/kg) was administered 2 h prior to the stressor. We found that ES/IS foot-shock stimulated similar robust increases in plasma adrenocorticotrophic hormone (ACTH) and corticosterone concentrations, and medial parvocellular division of the paraventricular nucleus (mpPVN) AVP and CRH hnRNA and c-fos mRNA levels in saline-treated ES/IS rats. Dexamethasone pretreatment suppressed ACTH and corticosterone levels similarly in IS and ES animals. Dexamethasone pretreatment also suppressed mpPVN CRH and AVP hnRNA levels at 30 min. However, by 120 min, the mpPVN AVP hnRNA levels in dexamethasone-treated rats were similar to those measured in the saline group. We also found that rats that received the most shocks on Day 1 had greater HPA axis activation on Day 2. We conclude that the magnitude of the foot-shock stressor, determined by learned and immediate cues, is important in determining the magnitude of the HPA response.     

Dissecting adrenal and behavioral responses to stress by targeted gene inactivation in mice

To define the molecular pathways modulating adrenal and behavioral responses to stress, we have generated mice with inactivation of hypothalamic neuropeptides and signaling pathways. Studies in mice deficient in corticotropin-releasing hormone (CRH) have revealed the essential role for CRH in adrenal glucocorticoid production in response to many physiological and psychological stressors. Immune system activation in CRH-deficient mice provides a unique exception to the necessity for CRH in stimulating adrenal glucocorticoid production. By analyzing mice deficient in interleukin-6 (IL-6) and CRH, we find that restoration of glucocorticoid output with inflammation is largely mediated by dysregulated IL-6 production. Current studies focus on identifying cellular and gene targets by which glucocorticoids regulate immune system function. In contrast to impaired adrenocortical responses to stress, CRH-deficient mice exhibit normal behavioral responses to stress. To determine signaling pathways that may contribute to the behavioral responses to stress, we have generated and analyzed mice deficient in adenylyl cyclase type 8 (AC8). AC8 deficient mice have intact adrenocortical responses to stress, but an inability to undergo stress-induced alterations in behavior.     

Congenital absence of vasopressin and age-dependent changes in ACTH and corticosterone stress responses in rats

The hypothalamic components of the hypothalamo-pituitary-adrenal axis (HPA) are corticotropin-releasing hormone (CRH) and vasopressin. To test the hypothesis that HPA regulation changes with age, we compared ether and bacterial lipopolysaccharide (LPS) injection induced stress reactions in adult and 10-day-old Brattleboro rats, which naturally lack vasopressin owing to mutation of the gene (di/di). The LPS stimulus was used also with V(1b) receptor antagonist pretreatment (SSR149415). In adult di/di or V(1b) pretreated rats, we observed normal pituitary and adrenocortical secretory responses, while in all 10-day-old rats stress-induced serum corticosterone increases were marked, but adrenocorticotropin (ACTH) increases were significantly smaller. Compared to control pups the adenohypophysis of the 10-day-old di/di rats responded normally to CRH, but their adrenal glands were hyper-responsive to ACTH, while in adults there was greater secretion at both levels with no difference between the genotypes. The serum transcortin level was higher in adults than pups, with the di/di pups having higher transcortin levels than controls. Hence, using the same stressors in adults and pups with both a genetic model and pharmacological pretreatment, we have shown that the role of vasopressin in ACTH regulation is more important during the neonatal period than in adulthood. Blunted hypophysial sensitivity to CRH and similar adrenal gland sensitivity to ACTH in the pups compared to adults suggest that hypothalamic factors could be responsible for the neonatal stress hyporesponsive period.     

Effect of Interleukin-1beta on Pituitary-Adrenal Responses and Body Weight in Neonatal Rats: Interaction with Maternal Deprivation

The hypothalamic-pituitary-adrenal (HPA) axis of the infant rat is normally hyporesponsive during postnatal days (pnd) four to fourteen. This interval is termed the stress hyporesponsive period (SHRP). The HPA axis, however, does respond to selective stimuli, such as interleukin-1beta (IL-1beta) during this period. Furthermore, maternal deprivation has been shown to alter the system so that it is responsive to mild stimuli. The present studies examined the interaction between 24 h of maternal deprivation and intraperitoneal administration of recombinant human (rh) IL-1beta (4 μg/kg) at 3 ages (i.e., pnd 6, 12, 18) during or after the SHRP. The results demonstrate that maternal deprivation modifies the response of the HPA axis induced by IL-1beta in an age-dependent fashion: 1) a greater response at pnd 6; 2) a quicker response at pnd 12; and 3) a suppressed response pattern at pnd 18. Moreover, these responses across ages differ as a function of maternal contact postinjection: 1) deprivation augments the ACTH and CORT response and maternal contact postinjection further augments this response at pnd 6; 2) deprivation increases the ACTH and CORT response to vehicle and the CORT response to IL-1beta in 12 day-old pups and the mother has a modest inhibitory effect; and 3) at pnd 18 deprivation leads to lower ACTH concentrations, but higher overall CORT levels and maternal contact postinjection effectively suppresses both the ACTH and CORT response to IL-1. These differences in the HPA response do not appear to be due to differences in the immune response. Plasma concentrations of endogenous rat IL-1beta determined 1 and 2 h after injection of rhIL-1beta were not modified by deprivation and were reduced at pnd 18 compared to pnd 6 and 12 in NDEP pups. Finally, IL-1beta reduced food intake, as reflected by a decrease in body weight, in deprived pups at all 3 ages. The findings in the present experiments suggest that there are additional pathways through which IL-1beta can act on the CNS to activate the HPA axis besides direct action at the hypothalamus.     

Inhibitory avoidance deficit following short-term adrenalectomy in the rat: the role of adrenal catecholamines

Impaired retention of an inhibitory avoidance response was observed in rats subjected to adrenalectomy (ADX) up to 120 hr before the single learning trial. Corticosterone substitution failed to normalize this behavioral deficit. Rats ADX 240 hr prior to the learning trial showed a normalized behavior. Adrenomedullectomy (ADXM) 48 or 240 hr before learning caused a similar impairment as in short-term ADX rats. The 240-hr ADX rats subjected to corticosterone substitution showed the same behavioral deficit as short-term ADX rats or ADXM ones. Immediate postlearning subcutaneous injection of adrenaline in a dose range of 0.005-5.0 micrograms/kg or of noradrenaline (0.005-0.5 microgram/kg) to 48-hr ADX rats resulted in a dose-related improvement of later retention behavior. Higher doses of catecholamines were less or ineffective. Postlearning treatment of 48-hr ADXM rats with adrenaline (0.5-500 micrograms/kg) caused a similar pattern of behavioral changes. It is concluded that adrenal catecholamines play an important role in the modulation of consolidation of memory. In addition, the high circulating ACTH levels that follow long-term ADX may correct for the behaviorial deficit induced by the absence of adrenomedullary catecholamines.     

Hypothalamo-pituitary-adrenocortical axis function and hedonic behavior in adult male and female rats prenatally stressed by maternal food restriction

Neuroendocrine activation during stress is affected by many factors contributing to the variability of the stress response. The present study was aimed at evaluating long-term changes in hypothalamo-pituitary-adrenocortical (HPA) axis function and in hedonic behavior in adult offspring prenatally stressed by maternal food restriction, with attention on possible gender differences. Adult offspring were blood sampled via a tail artery cannula. Prenatally stressed females had significantly higher adrenal weights compared to males. Plasma ACTH levels, which rose in response to acute stress induced by handling, were significantly higher in females compared to those in males. A similar pattern was found in plasma corticosterone. The rise in ACTH levels was more pronounced in prenatally stressed rats though the rise in corticosterone failed to be modified. Corticotropin releasing hormone (CRH) and proopiomelanocortin mRNA levels in the hypothalamic paraventricular nucleus and anterior pituitary, respectively, were found to be unchanged. The present experiments failed to reveal a decrease in hedonic behavior in prenatally stressed rats. In contrast, in male offspring a tendency to a higher sucrose preference was observed. These data together with observed changes in hormone and CRH mRNA levels indicate that the gestational stress used did not result in a depression-like state in adult offspring.     

Sex differences in prenatally programmed anxiety behaviour in rats: differential corticotropin-releasing hormone receptor mRNA expression in the amygdaloid complex

We recently reported that male, but not female, offspring born to mothers exposed to social stress during late gestation show heightened anxiety-type behaviour in adulthood. The amygdala organises anxious behaviour, which involves actions of corticotropin-releasing hormone (CRH). CRH gene expression and/or its release are increased in the amygdala in prenatally stressed (PNS) rats. CRH type 1 receptor (CRH-R1) mediates actions of CRH and urocortin I to promote anxiety-like behaviour, whereas the CRH type 2 receptor (CRH-R2) may mediate anxiolytic actions, through actions of urocortins 2 and 3. Here, using quantitative in situ hybridisation, we investigated whether altered CRH receptor mRNA expression in the amygdaloid nuclei may explain the sex differences in anxiety behaviour in adult male and female PNS rats. CRH-R1 mRNA expression was significantly greater in the central amygdala and basolateral amygdala (BLA) in male PNS rats compared with controls, with no change in the basomedial amygdala (BMA) or medial amygdala (MeA). In PNS females, CRH-R1 mRNA expression was greater than controls only in the MeA. Conversely, CRH-R2 mRNA expression was significantly lower in the BMA of male PNS rats compared with controls, but greater in female PNS rats, with no change in the BLA or MeA in either sex. The ratio of CRH-R1:CRH-R2 mRNA in the amygdaloid nuclei was generally increased in PNS males, but not in the PNS females. In conclusion, sex differences in anxiety-type behaviour in PNS rats may be explained by differential mRNA expression for CRH-R1 (pro-anxiogenic) and CRH-R2 (pro-anxiolytic) in the amygdaloid complex.     

Stress and Cytokine Effects on Learning: What Does Sex Have to Do With It?

Many studies have alluded to sexually dimorphic changes in behavior following stress. Although many have suggested that these changes are a function of stress-induced changes in learning and memory, there are questions regarding whether performance in those learning and memory tasks are influenced by stress-induced changes in drive more than in actual learning and memory processes. We used the classically conditioned eyeblink response (CCER) to determine whether slowed learning following stress in females can be explained by changes in unconditional response (UR) amplitude, a sign of a stress-induced shift in sensory reactivity. In addition, we had a second treatment group injected with the pro-inflammatory cytokine IL-1beta to serve as an interoceptive stress condition, a physiological stressor with minimal stimulation to the animal. Replicating the work by Shors and colleagues, we found that stressed female rats had slower acquisition of the conditioned response (CR), but we also found that an IL-1beta injection leads to a slowing of CR acquisition. However, in both cases, UR amplitude was lower in the treatment groups. We followed up these results by testing sensory reactivity through the acoustic startle response (ASR), where the magnitude of the ASR was marginally, but nonsignificantly, reduced by the same dose regimen of IL-1beta. Together, these experiments suggest that tailshock stress and immune signaling (IL-1beta) reduce sensory reactivity and the saliency of the stimuli used in the CCER, leading to slower learning in female rats.     

Neuropeptide and cardiovascular responses to intravenous catheterization in normotensive and hypertensive blacks and whites

Research suggests that heightened cardiovascular and neuroendocrine (typically catecholamine) responses to stressors may lead to the development of hypertension and that there may be race differences in patterns of reactivity that are potentially pathogenic. Certain neuropeptides exert profound effects on blood pressure (BP) and heart rate (HR), yet no published studies have examined relationships between these peptides, hypertensive status, race, and reactivity. Seventeen Black and 20 White normotensive and borderline-hypertensive male 19- to 50-year-olds underwent intravenous catheterization while cardiovascular and neuropeptide responses to the stress of being catheterized were examined. Results indicate that, in response to the stressor, Black hypertensives, showed significantly lower endorphin levels compared to Black normotensives, and White hypertensives showed significantly higher levels of beta-endorphin compared to White normotensives. Groups were not significantly different in endorphin levels at recovery. Black hypertensives also showed significantly higher stressor-induced HR and systolic and diastolic BP compared to White hypertensives and normotensives. Lower levels of beta-endorphin and lower urine sodium excretion were associated with higher BP and HR.     

Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats

Omega (n)-3 and n-6 fatty acids are important membrane components of neurons and immune cells, and related to psychiatric and inflammatory diseases. Increased ratio of n-6/n-3 in the blood has been reported in depressed patients and in students following stress exposure. The n-3 fatty acid, eicosapentaenoic acid (ethyl-EPA) suppresses inflammation and has antidepressant properties. Interleukin (IL)-1beta can stimulate corticosterone secretion, induce anxiety and stress-like behavior and inflammatory responses. This study was to evaluate the effect of diets enriched with coconut oil, ethyl-EPA and soybean oil on central IL-1beta induced stress and anxiety-like behavior, induced changes in the concentration of prostaglandin (PG) E2 and corticosterone and the release of IL-10. Groups of rats were fed with either 5% coconut oil (as control diet), 0.2% EPA with 4.8% coconut oil or 1% EPA with 4% coconut oil and 5% soybean oil for 7 weeks. The central administration of IL-1beta induced sickness, stress and anxiety-like behavior as indicated by a reduction in body weight, decreased time spent, and the number of entries, into the open arms of the elevated plus maze and decreased exploration and entry into the central zone of the "open field" apparatus. IL-1beta also increased PGE2 and corticosterone concentrations and decreased the release of IL-10 from leucocytes. Food enriched with ethyl-EPA but not soybean oil, significantly attenuated most of these changes. These results demonstrate that ethyl-EPA has anti-inflammatory, anti-stress and anti-anxiety effects in rats.     

Neonatal treatment with monosodium glutamate does not alter grooming behavior induced by novelty or adrenocorticotropic hormone

The increased grooming behavior observed in a novel environment has been attributed to release of peptides derived from proopiomelanocortin (POMC), such as ACTH, alpha-melanocyte-stimulating hormone (alpha-MSH), or beta-endorphin, which themselves can elicit grooming. This is because novelty-induced grooming is attenuated both by hypophysectomy and by antiserum to ACTH injected into the cerebral ventricles. Administration of monosodium glutamate (MSG) to neonatal rats destroys neurons in the arcuate nucleus of the hypothalamus, depleting the brain of POMC peptides, and also hypothalamic dopamine and choline acetyl-transferase activity. Neonatal MSG treatment did not significantly alter the grooming scores of adult rats in either home or novel environments compared to saline-treated animals. There were also no differences between MSG-and saline-treated rats in the grooming scores observed following graded doses of ACTH1-24 (0.2-1.0 micrograms) administered intracerebroventricularly. Thus if increased grooming in the novel environment is due to release into the ventricles of ACTH, alpha-MSH, beta-endorphin, these peptides more likely derive from the pituitary rather than from brain cells, although the failure of the MSG treatment to produce quantitative depletions of cerebral POMC peptides, especially in the brain stem, leaves open the latter possibility.     

The relationship between adrenal steroids and enrichment-induced brain growth.

The question of whether brain growth brought about by environmental enrichment is mediated by the adrenal cortex has not been answered. Accordingly, young male rats were either adrenalectomized (ADX) and infused with a constant maintenance dose of corticosterone (2 mg.kg-1.day-1) or sham-operated and implanted with a blank infusion device. Half of each surgical group was maintained in either impoverished (IC) or enriched conditions (EC). After 30 days, changes in forebrain growth and thickness of various cortical and subcortical regions were determined for each group. Enrichment and ADX independently increased forebrain weight and thickened cortical tissue at about the same anatomical sites. However, combined treatments were additive, not interactive. EC-induced brain growth is mimicked but not mediated by adrenalectomy.     

Does IL-6 release ACTH by exerting a direct effect in the rat anterior pituitary

Adult male rats were used to determine whether high circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) were capable of releasing ACTH independently of endogenous corticotropin-releasing factor (CRF). On one hand, CRF antibodies or a potent CRF antagonist significantly decreased, but did not totally abolish the ACTH response to the intravenous(i.v.) injection of recombinant rat IL-6. These results suggest that this cytokine might act either directly on the pituitary, or can release ACTH through mechanisms that do not involve CRF. On the other hand, the CRF antagonist or antibodies significantly (but not totally) blocked ACTH secretion due to the i.v. injection of endotoxin (LPS) while enhancing the ability of this immune stimulus to increase serum IL-6 concentrations. These results indicate that during endotoxemia, even very elevated circulating IL-6 concentrations were notable to release large amounts of ACTH in the absence of CRF drive. These data also illustrate the ability of a CRF antagonist or CRF antibodies to significantly augment IL-6 secretion,which indicates an inhibitory influence of the endogenous peptide in the paradigm we used.As comparable findings were obtained in adrenal-intact and adrenalectomized rats, they suggest that endogenous CRF is involved in the IL-6 response to LPS independently of circulating corticosteroids or other adrenal factors.     

Cytokine-Purine Interactions in Behavioral Depression in Rats

This paper reviews recent findings from our laboratories concerning metabolic and immune mediators of behavioral depression in rats. Specifically, a single injection of 6 mg/kg of reserpine substantially increases behavioral depression, as evidenced by an increase in the amount of time spent floating by independent groups of rats tested for swim performance at various times during the next week. The behavioral impairment consists of two components. An early component emerges one hour after reserpine treatment and persists for about 24 hours. The deficit is not reversed by intracranial ventricular infusion of the receptor antagonist for interleukin-1beta (IL-1beta). A second, late-component deficit appears approximately 48 hours after reserpine treatment and recovers within a week. Late-component depression is reversed by central infusion of the IL-1beta receptor antagonist, and is mimicked by central infusion of the proinflammatory cytokine. Importantly, both early and late components of reserpine-induced depression and IL-1beta induced depression are reversed by a systemic injection of the highly selective A2A adenosine receptor antagonist 8-(3-Chlorostyryl) caffeine. These data are discussed in terms of the overlap in the conservation-withdrawal reaction during sickness, traumatic stress, and major depression and the regional contribution of purines and cytokines to the organization of this reaction in the brain.     

Facilitated Acquisition of the Classically Conditioned Eyeblink Response in Male Rats After Systemic IL-1?

Exposure to inescapable stressors enhances cue-dependent learning in male rats; enhanced learning is apparent as facilitated acquisition of the classically conditioned eyeblink respouse (CCER). The proinflammatory cytokines, in particular interleukin (IL)-1beta, are presumed to orchestrate a number of acute-phase stress responses in rats, most notably fever, reduced feeding, and inactivity. Little is known of the impact proinflammatory cytokines have on learning and memory processes. Here, we address the effects of IL-1beta treatment on acquisition of the classically conditioned eyeblink response 2 hours [?] after injection in male rats. Training was accomplished with a delay-type paradigm (500-ms conditional stimulus coterminating with a 10-ms periorbital unconditional stimulation). Facilitated acquisition was clearly apparent in rats treated with IL-1beta (3.0 microg/kg). In a second experiment, we compared rats treated with 3.0 microg/kg to those treated with 1.0 microg/kg. Facilitated acquisition was reproduced, but the lower dose did not appreciably affect acquisition. These data further support contentions that IL-1beta has anxiogenic properties, affecting basic new motor learning in a manner similar to that observed after exposure to stress.     

Delta-sleep inducing peptide (DSIP) and ACTH (4-10) analogue influence fos-induction in the limbic structures of the rat brain under emotional stress

The effects of the ACTH (4-10) analogue, ACTH (4-7)-Pro-Gly-Pro, and delta-sleep inducing peptide (DSIP) on the induction of Fos immunoreactivity in the hypothalamic parvocellular paraventricular nucleus (pPVN) and limbic brain regions were studied in Wistar rats with high (resistant) or low (predisposed) resistance to emotional stress, predicted from differences in their open-field behaviour. Fos-immunoreactive (Fos-IR) cells were counted in brain sections automatically with a computer-based image analyser. Under basal conditions, Fos-IR cell numbers were greater in the pPVN in the predisposed rats, but were lower than in the resistant rats in the basolateral amygdala and medial and lateral septum. Intraperitoneal DSIP injection (30 μg/kg) increased basal Fos-IR cell number in the pPVN and lateral septum in resistant rats, with no effects in predisposed rats. ACTH (4-10) analogue (50 μg/kg)increased Fos expression in the pPVN in both resistant and predisposed rats, with essentially no effects in the basolateral amygdala or medial and lateral septum. Emotional stress (60 min restraint and intermittent subcutaneous electrical shocks) increased Fos expression in the pPVN and medial and lateral septum similarly in predisposed and resistant rats, but in the basolateral amygdala in only the predisposed rats. Intraperitoneal DSIP injection reduced the increases in Fos-IR cell number after emotional stress, particularly in predisposed rats. In predisposed rats DSIP decreased the number of Fos-IR cells in the pPVN and the medial and lateral septum, with no change in the basolateral amygdala. In resistant rats, DSIP decreased Fos expression only in the lateral septum. ACTH (4-10) analogue injection inhibited stress-induced Fos expression in the pPVN and the medial septum, but only in predisposed rats. The experiments indicate that DSIP and ACTH (4-10) analogue reduce pPVN and limbic neurone responses to emotional stress in the rats predisposed to emotional stress; the effects on Fos expression may play a role in the biological activities of these peptides.     

Plasma corticosterone and immune reactivity in restrained female C3H mice

Psychological stressors are known to stimulate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system resulting in the release of corticosterone and catecholamines respectively. They have also been reported to induce cytokine production. All these molecules affect various immune parameters and can alter overall immune competence of the individual. The purpose of this investigation was to study the regulation of the production of corticosterone during stress and its possible effects on immune reactivity. In a first series of experiments, the possible regulation of corticosterone production by interleukin (IL)-1beta and peripheral catecholamines during restraint was assessed using a pharmacological approach in mice. Plasma IL-1beta concentrations remained at basal after 1-h restraint and the stress-induced increase of plasma corticosterone was not modified by a peripheral injection of an IL-1 receptor antagonist (IL-1ra). By contrast, chemical sympathectomy potentiated the restraint-induced increase in plasma corticosterone concentration, this potentiation being reversed by IL-1ra. In a second series of experiments, the role of corticosterone in stress-immune relationships was studied in adrenalectomized mice subjected to restraint and immunized with sheep erythrocytes. Non-specific immunity, i.e. proliferation of splenocytes and thymocytes and plasma levels of IL-1beta, as well as specific immunity, i.e. antibody production and delayed hypersensitivity, were not altered after 2-h restraint. Adrenalectomy failed to induce immune effects in stressed animals, except that delayed hypersensitivity was stronger in adrenalectomized animals, revealing that the high levels of corticosterone produced during stress have an anti-inflammatory activity. The present data show that the stress-induced production of corticosterone was modulated by both peripheral catecholamines and IL-1beta. However, this production of corticosterone was unable to modulate immune reactivity except delayed hypersensitivity.