Stress differentially modulates mRNA expression for corticotrophin-releasing hormone receptors in hypothalamus,hippocampus and pituitary of prairie voles

This study compares the effect of an acute stressor (restraint for 1 h) versus a chronic stressor (social isolation for 4 weeks) on the expression of mRNAs for corticotropin-releasing hormone (CRH), CRH receptor type 1 (CRH-R1) and type 2 (CRH-R2) in the hypothalamus, hippocampus and pituitary of socially monogamous female prairie voles (Microtus ochrogaster). Animals were studied immediately following a stressor or as a function of repairing with a familiar sibling. Despite elevated expression of CRH mRNA, no alteration of CRH-R1 mRNA in the hypothalamus was observed following restraint stress or 4 weeks of social isolation. Hypothalamic CRH-R2 mRNA was significantly lower in voles exposed to restraint or isolation. CRH-R2 mRNA also remained down-regulated in isolated animals when these animals were re-paired with their sibling for one day following 28 days of isolation. Restraint, but not isolation, significantly increased CRH-R1 mRNA and decreased CRH-R2 mRNA in the pituitary. However, these differences were no longer observed when these animals were re-paired with their sibling for one day. Despite elevated CRH mRNA expression, CRH-R1 mRNA did not increase in the hippocampus following restraint or social isolation. Social isolation, but not restraint stress, increased CRH-R2 mRNA in the hippocampus, when these animals were re-paired with their sibling for one day the modulation of CRH mRNA remained up-regulated. Plasma corticosterone was elevated only following restraint, and not in animals that were handled, isolated or re-paired. The results of the present study reveal that acute restraint as well as social isolation can have significant consequences for the modulation of gene expression for the CRH receptors in brain and pituitary of prairie voles.     

IL-1beta immunoreactive neurons in the human hypothalamus: reduced numbers in multiple sclerosis

Corticotropin-releasing hormone (CRH)-containing neurons in the paraventricular nucleus (PVN) in the hypothalamus of multiple sclerosis (MS) patients are hyperactivated. Since interleukin-1 (IL-1)beta is a powerful activator of CRH neurons, its immunohistochemical expression was studied in the postmortem hypothalamus of MS patients (n=11) and matched controls (n=11). Hypothalamic tissue of 10/11 MS patients showed demyelinating lesions that in many cases contained IL-1beta-immunoreactive (ir) macrophages and glial cells. In control subjects IL-1beta-ir was only sporadically found in glial cells. Interestingly, abundant IL-1beta-ir was also present in hypothalamic neurons. Neuronal IL-1beta co-localised with oxytocin and not with vasopressin or CRH. IL-1beta clearly yielded a less intense staining in neurons and numbers of IL-1-ir neurons in the PVN were 4.5-fold reduced in MS. We suggest that IL-1beta produced by activated glial cells in the hypothalamus of MS patients may contribute to the activation of the hypothalamic CRH neurons, while reduced expression of neuronal IL-1beta in MS patients may have consequences for neuroendocrine, behavioural or autonomic functioning.     

Synergistic and additive actions of a psychosocial stressor and endotoxin challenge: Circulating and brain cytokines, plasma corticosterone and behavioral changes in mice

Activation of the inflammatory immune response may provoke neuroendocrine and central neurochemical effects that are reminiscent of those elicited by traditional stressors, and when administered concurrently may have synergistic effects. The present investigation assessed whether a psychosocial stressor, comprising social disruption, would augment the effects of lipopolysaccharide in mice. It was indeed observed that the social disruption engendered by a period of 2-4 weeks of social isolation (but not 1-7 days of this treatment) followed by regrouping, enhanced the effects of lipopolysaccharide (LPS: 10mug) in the provocation of sickness behavior, as well as plasma corticosterone, IL-6, TNF-alpha and IL-10 levels. Similar effects were not apparent with respect to IL-1beta, IL-4, or IFN-gamma. Synergy between LPS and other stressors (restraint, tail pinch, and loud noise) was not apparent with respect to sickness or plasma corticosterone, provisionally suggesting that social stressors, such as regrouping, may be more powerful or may engage unique neural or neuroendocrine circuits that favour synergistic outcomes. Within the CNS, the LPS and the regrouping stressor synergistically enhanced NE utilization within the prefrontal cortex, and additively influenced hippocampal NE utilization. In contrast to the effects on circulating cytokines, the LPS-induced elevation of IL-1beta, IL-6 and TNF-alpha mRNA expression in the hippocampus, PFC and nucleus tractus solitarius was diminished in animals that had experienced the regrouping stressor. In view of the combined actions of LPS challenge and a social stressor, these data are interpreted as suggesting that models of depression based on immune activation ought to consider the stressor backdrop upon which immune challenges are imposed.     

Effects of social isolation on mRNA expression for corticotrophin-releasing hormone receptors in prairie voles

Previous studies have demonstrated that various type of stressors modulate messenger ribonucleic acid (mRNA) for type 1 corticotropin-releasing hormone (CRH) receptor (CRH-R1 mRNA) and type 2 CRH receptor (CRH-R2 mRNA). The purpose of this study was to explore the effect of social isolation stress of varying durations on the CRH, CRH-R1 and CRH-R2 mRNAs expression in the hypothalamus, hippocampus and pituitary of socially monogamous female and male prairie voles (Microtus ochrogaster). Isolation for 1h (single isolation) or 1h of isolation every day for 4 weeks (repeated isolation) was followed by a significant increase in plasma corticosterone levels. Single or repeated isolation increased hypothalamic CRH mRNA expression, but no changes in CRH-R1 mRNA in the hypothalamus were observed. Continuous isolation for 4 weeks (chronic isolation) showed no effect on hypothalamic CRH or CRH-R1 mRNAs in female or male animals. However, hypothalamic CRH-R2 mRNA was significantly reduced in voles exposed to chronic isolation. Single or repeated isolation, but not chronic isolation, significantly increased CRH-R1 mRNA and decreased CRH-R2 mRNA in the pituitary. Despite elevated CRH mRNA expression, CRH-R1 and CRH-R2 mRNAs were not modulated in the hippocampus following single or repeated isolation. Although, chronic isolation did not affect hippocampal CRH or CRH-R1 mRNAs, it did increase CRH-R2 mRNA expression in females and males. The results of the present study in prairie voles suggest that social isolation has receptor subtype and species-specific consequences for the modulation of gene expression for CRH and its receptors in brain and pituitary. Previous studies have revealed a female-biased increase in oxytocin in response to chronic isolation; however, we did not find a sex difference in CRH or its receptors following single, repeated or chronic social isolation, suggesting that sexually dimorphic processes beyond the CRH system, possibly involving vasopressin, might explain this difference.     

Interleukin-2 stimulates the secretion of arginine vasopressin but not corticotropin-releasing hormone from rat hypothalamic cells in vitro

Cytokines are involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, thus providing a means of communication between the immune and neuroendocrine systems. In this study IL-2 caused a dose-dependent stimulation of AVP secretion from both the intact rat hypothalamus in vitro and hypothalamic cell cultures. IL-2 did not increase the secretion of CRH in either preparation, nor did it prime the cells to respond to a subsequent dose of IL-2. Both preparations, however, were able to respond to known CRH secretagogues such as 5-HT and 56 mM K⁺. This may provide yet another line of communication between the immune and neuroendocrine systems.     

Release of hypothalamic corticotropin-releasing hormone and arginine-vasopressin by interleukin 1β and αMSH: studies in rats with different susceptibility to inflammatory disease

The susceptibility of Lewis rats is related to blunted hypothalamic-pituitary-adrenal (HPA) axis responsiveness to a variety of inflammatory and neuroendocrine stimuli. In contrast resistance to inflammatory disease of histocompatible Fischer rats is associated with their intact HPA axis responses to the same stimuli. We have examined the contribution of IL-1β to in vitro corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) release from hypothalamic explants derived from LEW/N and F344/N rats. The same animal model has been used to investigate the regulatory effect of αMSH, an immunosuppressive neurohormone, on IL-1β stimulated CRH and AVP secretion. CRH basal release in both strains was similar. However, LEW/N hypothalamic AVP basal secretion was significantly elevated. CRH relative response of LEW/N hypothalamic explants to IL-1β stimulation was lower compared to Fischer, which is consistent with their hyporesponsiveness to inflammatory mediators. AVP secretion however, was significantly decreased in hypothalamic explants from both strains after 40 min exposure to IL-1β. αMSH suppressed basal CRH and AVP release in both LEW/N and F344/N rats and prevented IL-1β stimulated CRH secretion in these strains. AVP was further diminished in F344/N explants following incubation with αMSH+IL-1β, while LEW/N level was significantly elevated. However, AVP levels remained significantly below baseline in explants from both strains after final incubation with IL-1β. Although our findings indicate a modulatory action of αMSH in HPA axis regulation in vitro, the physiological importance of this phenomenon in Lewis and Fischer rats requires further investigation.     

Interleukin-1beta mediates the memory impairment associated with a delayed type hypersensitivity response to bacillus Calmette-Guérin in the rat hippocampus

Interleukin-1beta (IL-1beta) plays a major role in the initiation and exacerbation of brain inflammation, and its action is limited by the natural antagonist of IL-1 receptors, IL-1Ra. The aim of the present study was to test the hypothesis that IL-1beta mediates the functional consequences of inflammation during the course of delayed-type hypersensitivity response to bacillus Calmette-Guérin (BCG) in the hippocampus of Lewis rats. Animals were primed with an injection of BCG in the right hippocampus and challenged 4 weeks later with BCG administered subcutaneously. Concentrations of IL-1beta and IL-1Ra were measured by ELISA in the BCG injected hippocampus and compared to those measured in the contralateral hippocampus during the first 2 weeks post-challenge. IL-1beta levels increased in response to BCG challenge and peaked 12 days after challenge. The same variations appeared in the contralateral hippocampus but to a lesser extent. Hippocampal IL-1Ra levels increased in response to intrahippocampal injection of BCG. They further increased at days 6 and 9 post-challenge and decreased from day 12 back to baseline values on day 16. The increase in IL-1beta levels and the decline in IL-1Ra levels were associated with an impairment in spatial memory in a Y-maze on day 16 post-challenge, that was abrogated by chronic administration of IL-1Ra via a subcutaneously implanted osmotic minipump geared to deliver 7 mg IL-1Ra/day. These results show that overexpression of IL-1beta in the brain during the course of a chronic inflammation has deleterious consequences on cognitive processes, that are reversed by blockade of IL-1 receptors.     

Social instability in adolescence alters the central and peripheral hypothalamic-pituitary-adrenal responses to a repeated homotypic stressor in male and female rats

There has been little research on effects of chronic stressors on neuroendocrine function in adolescence despite increasing evidence of enduring effects of stressors during this period on behaviour in adulthood. We previously reported that social stress (SS: daily 1 h isolation and new cage partner for 16 days) in adolescence altered locomotor responses to psychostimulants in adulthood. Here, we investigated neuroendocrine responses over the duration of the procedure that may underlie the enduring effects of SS. SS rats were compared to rats undergoing daily isolation only (ISO) and controls (CTL) to determine responses to acute and repeated isolation with and without social instability. At 30 days of age (first isolation), higher plasma corticosterone and corticotrophin-releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus and in the central nucleus of the amygdala (CeA) were found in males caged with a new partner (SS) after isolation than those returned to their original partner (ISO). On day 45, SS males and females showed less habituation (higher bioactive levels of corticosterone based on plasma corticosterone and corticosteroid binding globulin levels) to the 16th episode of isolation than did ISO. SS and ISO had higher baseline expression of CRH mRNA in the PVN on day 45 than did CTL, and only CTL had increased levels after isolation. CRH mRNA expression in the CeA increased to a first isolation in CTL and to a 16th isolation in SS but not in ISO males. Modest differences in social interactions were observed between SS and ISO when returned to their cages after isolation. The results suggest that mild social stressors in adolescence impede neuroendocrine adaptation to homotypic stressors. The resultant increase in exposure to glucocorticoids over adolescence may alter ongoing brain development and increase vulnerability to psychopathology.     

Brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis adaptation processes in a depressive-like state induced by chronic restraint stress

Depression is potentially life-threatening. The most important neuroendocrine abnormality in this disorder is hypothalamo-pituitary-adrenocortical (HPA) axis hyperactivity. Recent findings suggest that all depression treatments may boost the neurotrophin production especially brain-derived neurotrophic factor (BDNF). Moreover, BDNF is highly involved in the regulation of HPA axis activity. The aim of this study was to determine the impact of chronic stress (restraint 3 h/day for 3 weeks) on animal behavior and HPA axis activity in parallel with hippocampus, hypothalamus and pituitary BDNF levels. Chronic stress induced changes in anxiety (light/dark box test) and anhedonic states (sucrose preference test) and in depressive-like behavior (forced swimming test); general locomotor activity and body temperature were modified and animal body weight gain was reduced by 17%. HPA axis activity was highly modified by chronic stress, since basal levels of mRNA and peptide hypothalamic contents in CRH and AVP and plasma concentrations in ACTH and corticosterone were significantly increased. The HPA axis response to novel acute stress was also modified in chronically stressed rats, suggesting adaptive mechanisms. Basal BDNF contents were increased in the hippocampus, hypothalamus and pituitary in chronically stressed rats and the BDNF response to novel acute stress was also modified. This multiparametric study showed that chronic restraint stress induced a depressive-like state that was sustained by mechanisms associated with BDNF regulation.     

Microinfusion of a corticotrophin-releasing hormone receptor 1 antisense oligodeoxynucleotide into the dorsal hippocampus attenuates stress responses at specific times after stress exposure

Corticotrophin-releasing hormone (CRH) plays a key role in the adjustment of neuroendocrine and behavioural adaptations to stress. Dysregulation in CRH systems has been implicated in a variety of stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD). The present study examined the relationship between stress-induced PTSD-like behavioural response patterns and levels of CRH, CRH receptor (CHR-R)1 and phosphorylated extracellular signal-regulated kinase (pERK1/2) in the rat hippocampus subregions. The effects of pharmacological manipulations on behavioural, physiological and response patterns of brain-derived neurotrophic factor (BDNF) and pERK1/2 expression using a CRH receptor (CRH-R)1-antisense oligodeoxynucleotide (CRH-R1-ASODN) were evaluated. CRH and CRH-R1 mRNA and pERK1/2 protein levels were assessed in the hippocampus subregions 7 days after exposure to predator scent stress (PSS). The effects of CRH-ASODN versus CRH-Scrambled-ODN microinfusion to the dorsal hippocampus either 1 h or 48 h post-exposure on behavioural tests (elevated plus maze and acoustic startle response) were evaluated 7 days later, 14 days after PSS exposure. Localised brain expression of BDNF and ERK1/2 was subsequently assessed. All data were analysed in relation to individual behaviour patterns. A distinct pattern associated with extreme behavioural response (EBR) was revealed in the bioassay of behavioural study subjects, classified according to their individual patterns of behavioural response at 7 days. These EBR individuals displayed significantly higher CRH and CRH-R1 mRNA levels in the CA1 and CA3 areas, mediating down-regulation of pERK1/2 protein levels. Microinfusion of a CRH-R1-ASODN into the dorsal hippocampus 48 h after stress exposure, although not immediately after exposure (1 h), significantly reduced behavioural disruption and was associated with concomitant up-regulation of BDNF and pERK1/2 protein levels compared to CRH-R1-Scrambled -ODN controls. CRH/CRH-R1 is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.     

Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups,independently of hypothalamic and peripheral cytokine levels

Adult animals subjected to chronic stress show an inflammatory response in the hippocampus which has been related to cognitive dysfunction and psychopathology. However the immediate consequences of early life stress on hippocampal glial cells have not been studied. Here we analyzed the effects of maternal separation (MS) on astrocyte and microglial cell morphology in the hippocampal hilus, compared the expression of cytokines in the hippocampus and hypothalamus, and the peripheral response of cytokines, on postnatal day (PD) 15.Male rat pups of MS (3 h/day, PD1–PD14) and Control (CONT) pups showed similar microglial cell densities in the hilus, but MS pups presented more activated microglia. MS decreased astrocyte density and the number of processes in the hilus. Cytokine mRNA expression (qPCR) was analyzed in MS and CONT groups, sacrificed (i) under basal (B) conditions or (ii) after a single stress event (SS) at PN15. In hippocampal extracts, MS increased IL-1β mRNA, under B and SS conditions while IL-6 and TNF-α did not change. In hypothalamic tissue, MS increased TNF-α and IL-6 mRNA, but not IL-1b, after SS. Peripheral concentrations of IL-1β were decreased under B and SS conditions in MS; IL-6 concentration increased after SS in MS pups, and TNF-α concentration was unchanged. In conclusion, MS activates microglial cells and decreases astrocyte density in the hippocampus. A differential cytokine expression is observed in the hippocampus and the hypothalamus after MS, and after SS. Also, MS triggers an independent response of peripheral cytokines. These specific responses together could contribute to decrease hippocampal neurogenesis and alter the neuroendocrine axis.     

Neutrophil-activating peptide-1/interleukin-8 mRNA is localized in rat hypothalamus and hippocampus.

Neutrophil-activating peptide-1/interleukin-8 (NAP-1/IL-8) is a cytokine synthesized by various cell types. In the immune system NAP-1/IL-8 is part of an immune cascade initiated by IL-1 production. NAP-1/IL-8 affects hypothalamic function and its production is suppressed by steroids. Therefore, it might be expected that NAP-1/IL-8 would be produced in brain areas involved in the control of the hypothalamic-pituitary-adrenocortical axis (HPA). NAP-1/IL-8 mRNA was localized by in situ hybridization in the paraventricular nucleus of the hypothalamus and hippocampus. Those areas also express the genes encoding interleukin-1-alpha (IL-1 alpha), IL-1 beta, IL-1 receptors, and IL-1 receptor antagonist (IL-1ra). This suggests that an immune cascade, which is well characterized in the immune system, may exist in brain, in areas of relevance to the regulation of stress-related neuroendocrine function.     

Interleukin-18 displays effects opposite to those of interleukin-1 in the regulation of neuroendocrine stress axis

The effects of interleukin-18 (IL-18), a putative member of the IL-1 family, were investigated on basal and stimulated release of corticotropin-releasing hormone (CRH) and prostanoids from rat hypothalamic explants and glial cells in vitro. We found that IL-18 decreases basal and KCl-stimulated CRH release from the hypothalamus. IL-18 also reduced CRH gene expression after 1- and 3-h incubation. The cytokine did not modify basal PGE2 production by hypothalamic explants but abolished production stimulated by IL-1β. Similar effects were also observed on cultured glial cells. The present findings show that IL-18 possesses a profile of in vitro neuroendocrine activities opposing to, and even antagonizing, those of IL-1β.     

Lipopolysaccharide and a social stressor influence behaviour, corticosterone and cytokine levels: divergent actions in cyclooxygenase-2 deficient mice and wild type controls

Administration of the endotoxin, lipopolysaccharide (LPS) diminished motor activity and increased plasma corticosterone as well as circulating levels of interleukin-1beta (IL-1beta), IL-6, tumor necrosis-factor-alpha (TNF-alpha) and IL-10. Among cyclooxygenase-2 (COX-2) knockout mice the behavioural, corticosterone and cytokine variations promoted by LPS were moderately (home cage activity, corticosterone, TNF-alpha) or largely (IL-6) reduced. However, if mice were exposed to a psychosocial stressor (social disruption associated with grouping mice with novel cage-mates after a period of isolation) coupled with LPS treatment, then the effects of the COX-2 deletion were absent, or there was a synergistic or additive elevation apparent (e.g., in the case of TNF-alpha, IL-6 and corticosterone). Evidently, COX-2 deletion may have either pro- or anti-inflammatory actions, depending upon the psychosocial context in which immune activation occurs.     

Chronic administration of tianeptine balances lipopolysaccharide-induced expression of cytokines in the spleen and hypothalamus of rats

The antidepressant tianeptine has been shown to protect the hippocampus against the deleterious consequences of stress and to attenuate the behavioral and neuroendocrine effects of the cytokine inducer lipopolysaccharide (LPS). Since sickness symptoms are linked to peripheral and brain production of cytokines and pro-inflammatory cytokines can promote neurotoxicity, the present study was undertaken to test the possibility that tianeptine attenuates production of pro-inflammatory cytokines. This hypothesis has been tested by studying the effects of a chronic intraperitoneal (i.p.) administration of tianeptine (10 mg/kg twice a day for 21 days) to rats on the induction by LPS (250 microg/kg, i.p.) of the production of pro- and anti-inflammatory cytokines, at the periphery (spleen, pituitary) and in the brain (hypothalamus, hippocampus). The expression of mRNAs coding for IL-1 beta, TNF-alpha, IL-6 or IL-10 (RT-PCR) and plasma levels of IL-1 beta, TNF-alpha and IL-10 (ELISA) were measured at various time intervals following LPS. Chronic tianeptine treatment attenuated LPS-induced expression of TNF-alpha in the spleen as well as plasma levels of this cytokine and altered the central balance between pro- and anti-inflammatory cytokines (IL-1 beta/IL-10). These results open new vistas in the pharmacological activity of tianeptine and provide further insights on the possible mechanisms of action involved in its neuroprotective properties.     

Chronic corticotropin-releasing hormone and vasopressin regulate corticosteroid receptors in rat hippocampus and anterior pituitary

Corticotropin-releasing hormone (CRH) and vasopressin (AVP) participate in the endocrine, autonomic, immunological and behavioral response to stress. CRH and AVP receptors are found in hippocampus and anterior pituitary, where mineralocorticoid (MR) and glucocorticoid (GR) receptors are abundant. We investigated the possible influence of CRH and AVP on the regulation of MR and GR in both tissues. CRH, AVP, or their antagonists were administered to adrenalectomized rats substituted with corticosterone, to avoid interference with adrenal secretion. Repeated i.c.v. oCRH injections (10 microgram) for 5 days significantly decreased MR and GR mRNA in hippocampus and MR mRNA in anterior pituitary. AVP significantly increased both corticosteroid receptor mRNAs, as repeated i.c.v. injections (5 microgram) for 5 days in hippocampus, and as continuous i.c.v. infusion (10 ng/h/5 days) in anterior pituitary. The i.c.v. infusion of 5 or 10 microgram/day of the alpha-helical CRH antagonist during intermittent restraint stress (5 days), induced a significant decrease in hippocampal MR binding. In anterior pituitary, 5 microgram/day significantly decreased MR binding, while 10 microgram/day significantly increased GR binding. Under the same conditions of stress, the infusion of 15 microgram/day of the vasopressin V1a/1b receptor antagonist [dP Tyr (Me)(2)AVP] significantly increased MR and GR binding in hippocampus and anterior pituitary; 5 microgram/day significantly decreased pituitary MR binding. Our results show that CRH and AVP regulate MR and GR in hippocampus and anterior pituitary. This reveals another important function of CRH and AVP, which could be relevant to understand stress adaptation and the pathophysiology of stress-related disorders like major depression.     

Influence of poly I:C on sickness behaviors, plasma cytokines, corticosterone and central monoamine activity: moderation by social stressors

Stressor and cytokine challenges provoke several common effects, and may synergistically influence behavioral and neurochemical functioning. In the present investigation, we assessed whether the effects of poly I:C would be influenced when administered on a backdrop of a psychosocial stressor. In naïve mice, poly I:C (2 mg/kg) modestly increased sickness behaviors, plasma IL-6, TNF-α and IL-10 levels, but did not affect IL-1, IL-4, or IFN-γ. The viral analogue also increased plasma corticosterone levels and norepinephrine (NE) utilization within the paraventricular hypothalamus (PVN) and hippocampus. However, among mice that had experienced social disruption (comprising 14 days of isolation followed by regrouping), the behavioral, IL-6, IL-10, and corticoid alterations provoked by poly I:C were markedly augmented. Moreover, following social disruption the effect of poly I:C on NE utilization was increased within the PVN, prefrontal cortex and central amygdala, as was serotonin utilization within the hippocampus. The effects of poly I:C were likewise augmented following social disruption engendered by introducing mice to strangers.. However, among mice that had previously been exposed to a chronic, variable psychosocial stressor regimen, the augmented behavioral, neuroendocrine and monoamine effects of poly I:C were absent, and IL-6 and IL-10 levels were reduced relative to mice that had not been chronically stressed. In contrast, levels of IL-1β and IFN-γ were increased. Mechanisms that might be responsible for the interactive effects of social disruption and immune activation are presented, and the data were related to depressive symptoms associated with stressor and cytokine treatments.     

Chronic exposure to morphine attenuates expression of interleukin-1β in the rat hippocampus

The cytokine, interleukin-1β (IL-1β), can modulate both immune and neuroendocrine events. Alteration of IL-1β expression by exogenous factors, such as morphine, may affect the neuro-endocrine-immune axis. Brain sections from male rats implanted with either morphine or placebo pellets were stained for IL-1β immunoreactivity. The results showed pronounced attenuation of IL-1β immunoreactivity in the dentate gyrus and the CAl-CA3 fields of the hippocampus in morphine-implanted rats compared to placebo controls. It has been suggested that the hippocampus is involved in the regulation of hypothalamic activity. Attenuation of IL-1β expression in the hippocampus by chronic exposure to morphine may be one of the mechanisms underlying the neuro-endocrine-immune modulatory effects of opiate addiction.