The function of the adrenocortical axis in permanent middle cerebral artery occlusion: effect of glucocorticoids on the neurological outcome.

We characterized the effect of acute ischemic stroke on the activation of the hypothalamic-pituitary-adrenal (HPA) axis and evaluated the role of glucocorticoids (GC) in the clinical outcome following ischemic stroke. Male spontaneous hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and developed a cortical infarct. At 4h post-PMCAO or sham operation, serum levels of ACTH and corticosterone (CS) were elevated 5 and 4 fold respectively as compared to controls and then returned to basal levels at 24h post surgery. In these experimental groups we found also a significant depletion of median eminence (ME)-CRH(41). In adrenalectomized (Adx) rats that underwent PMCAO the degree of motor disability and infarct volume was similar to that of intact rats. Administration of dexamethasone (Dex) to Adx-PMCAO rats significantly improved the motor disability and decreased the infarct volume. However, in sham-Adx with PMCAO, Dex had no effect on these two parameters. In rats with PMCAO or sham-PMCAO, brain production of PGE(2) was significantly increased. This effect was further enhanced in Adx-PMCAO rats and significantly inhibited by Dex. In conclusion, activation of the HPA axis following PMCAO is due to stress induced by surgery. This activation is mediated by hypothalamic CRH(41). Absence of endogenous GC or administration of Dex in naïve rats does not alter motor and pathological parameters in the acute stage following PMCAO. In contrast, administration of Dex significantly improved the outcome following cerebral ischemia in Adx rats which may be due to increased glucocorticoid receptors. Brain production of PGE(2) does not play an important role in the pathophysiology of the acute phase of cerebral ischemia.

Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression.

Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1 beta levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1 beta via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions.

Interleukin-1 signaling modulates stress-induced analgesia.

Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed "stress-induced analgesia" (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. Another group of C57 mice was acutely administered with IL-1 receptor antagonist (IL-1ra). Mice were exposed to 2min swim stress at one of three water temperatures: 32 degrees C (mild stress), 20-23 degrees C (moderate stress), or 15 degrees C (severe stress); and then tested for pain sensitivity using the hot-plate test. Corticosterone levels were assessed in separate groups of WT and mutant mice following exposure to the three types of stress. Mild stress induced significant analgesia in the two WT strains and saline-treated mice, but not in the mutant strains or the IL-1ra-treated mice. Similarly, mild stress induced significantly elevated corticosterone levels in WT mice, and blunted corticosterone response in mutant mice. In contrast, both WT and mutant strains, as well as IL-1ra-treated mice, displayed analgesic and corticosterone responses following moderate and severe stress. Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.

Differential response to acute and repeated stress in cannabinoid CB1 receptor knockout newborn and adult mice.

Previous studies have suggested that the endocannabinoid CB1 receptor (ECBR) system is involved in stress. However, the nature of this association is complex. Here, we investigated the role of CB1 receptors in the response to stress by comparing the effects of various stress modalities in CB1-/- receptor deficient and wild-type mice, at adulthood and during early development. Response to acute stress was assayed by plasma corticosterone (CS) and adrenocorticotrophic hormone (ACTH), USVs and motor inhibition. The response to repeated stress was assessed by USVs and motor inhibition. Since repeated bell stress seemed to cause a cumulative fear in CB1 receptor knockout mice, these behavioral responses were also compared to those observed after a single severe stress (forced swimming). In wild-type, but not in CB1 receptor knockout mice, bell stress-induced elevations of ACTH and CS were significant. The first exposure to bell stress had no significant effect on USVs or mobility. Upon repeated exposures, significant suppression of USVs, together with behavioral inhibition, were observed in CB1 knockout but not in wild-type mice. Swim stress inhibited USVs in the knockout animals, and the profound motor inhibition displayed by all animals was greater and more prolonged in the CB1-/- mice. Since the knockout mice lack the CB1 receptor throughout pre- and postnatal life, the stress response in pups was also assayed (by separation-induced USVs). Wild-type pups displayed the characteristic developmental peak in USV emissions; it was completely lacking in knockout pups. We conclude that acutely, the absence of CB1 receptors reduces the neuroendocrine response and does not affect the behavioral response to moderate stress. However, upon repeated stress or acute severe stress, CB1 receptor deficiency causes persistent behavioral inhibition. Finally, the CB1 receptor plays a role in modulating the stress response from an early age. These observations suggest that CB1 receptors participate in the mediation of the stress response and that the absence of these receptors results in a greater vulnerability to stress. We suggest that the stress-induced endocrine and behavioral suppression in CB1 receptor deficient mice may serve as a model for some forms of post-traumatic stress disorder (PTSD). Further, the role of CB1 receptors in coping with stress is a lifelong function. Finally, although equivalent research has not been performed in human infants, the postnatal suppression of the stress response in CB1 receptor knockout pups may have implications when cannabinoid-based therapy is considered for children.

Diverse effects of stress and additional adrenocorticotropic hormone on digitalis-like compounds in normal and nude mice.

Digitalis-like compounds (DLC) are steroidal hormones that are synthesized in, and released from, the adrenal gland, whose regulation may be directed by the hypothalamic-pituitary-adrenal (HPA) axis. Increasing evidence points to antitumour properties of these compounds and we hypothesized that the establishment of tumours in athymic nude mice may be facilitated by an abnormal synthesis or secretion of DLC. To explore this hypothesis, DLC concentrations were determined in the plasma, and in adrenal and hypothalamic tissues of nude compared to normal mice under basal conditions, and 30 min after a stress stimulus (i.p. injection of 100 micro l saline) with or without additional adrenocorticotropic hormone (ACTH) 1 micro g/per animal. Simultaneously, plasma corticosterone and serum adrenocorticotropic hormone (ACTH) concentrations were analysed. The basal DLC concentrations were similar in the plasma and the hypothalamus of both strains, whereas the basal adrenal DLC concentration was significantly lower in the nude mice compared to normal mice. The stress stimulus induced in normal mice a significant increase in DLC concentrations in the adrenal gland, the plasma and the hypothalamus. However, in nude mice, it caused an increase only in the adrenal gland and the hypothalamus, whereas the plasma DLC concentration was not affected. In both strains, the administration of ACTH in addition to injection stress did not provoke a further increase in DLC concentrations while inducing a significant increase in plasma corticosterone concentration. Regardless of the applied stimulus, the nude mice expressed significant lower DLC concentrations in the adrenal gland and the plasma compared to normal mice. The low basal adrenal DLC concentration in nude mice and their impaired DLC response towards stress- and ACTH stimulation both support an involvement of DLC in tumorigenesis.

The role of endogenous interleukin-1 in stress-induced adrenal activation and adrenalectomy-induced adrenocorticotropic hormone hypersecretion.

To examine the role of IL-1 in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis, mice with knockout of the IL-1 receptor type I (IL-1rKO) were exposed to psychological and metabolic stressors. When exposed to mild stressors (auditory stress or a low dose of 2-deoxyglucose), IL-1rKO mice displayed a significantly diminished corticosterone secretion, compared with wild-type (WT) controls. In response to more severe stressors (60-min restraint or a high dose of 2-deoxyglucose), both groups exhibited a similar increase in corticosterone secretion. To examine the role of IL-1 in HPA axis feedback regulation, serum ACTH levels were measured after adrenalectomy (ADX) in IL-1rKO mice and in mice with transgenic overexpression of IL-1 receptor antagonist within the brain (IL-1raTG). As expected, WT controls exhibited ADX-induced ACTH hypersecretion, whereas IL-1rKO and IL-1raTG mice showed no increase in ACTH levels, suggesting that brain IL-1 has a critical role in ADX-associated ACTH hypersecretion. Similarly, WT mice that were chronically exposed to IL-1ra in utero displayed a diminished ADX-induced ACTH hypersecretion, compared with vehicle-treated controls, suggesting a developmental role of IL-1 in HPA axis regulation. In conclusion, our results suggest that endogenous IL-1 plays a critical role in HPA axis activation after stress and ADX.

The EAE-associated behavioral syndrome: I. Temporal correlation with inflammatory mediators.

To elucidate the mechanisms underlying the EAE-associated behavioral syndrome (EBS), we examined the temporal correlation between the behavioral alterations and inflammatory processes. Onset of the behavioral syndrome was associated with the onset of brain infiltration, as well as mRNA expression of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) and elevated production of interleukin 1 beta protein and prostaglandin E(2) (PGE(2)). Sickness behavior symptoms coincided with peak cytokine expression. Behavioral recovery was associated with a reduction of cytokine expression, but not infiltration, PGE(2) production or motor disturbances. These results suggest that inflammatory processes in general, and the production of pro-inflammatory cytokines in particular, are involved in mediating EAE-associated sickness behavior.

Virus and host factors that mediate the clinical and behavioral signs of experimental herpetic encephalitis. A short auto-review.

Experimental models that mimic the clinical syndrome of human viral encephalitis and represent HSV-1 neurotropism were utilized to investigate neuro-pharmacologic changes mediating clinical and behavioral manifestations of encephalitic infection of the central nervous system with HSV-1-induced rapid activation of the hypothalamic--pituitary--adrenocortical (HPA) axis and production of brain derived interleukin-1 (IL-1) and prostaglandin E2 (PG-E2), independently of viral replication. HSV-1 infection induced clinical signs of fever, motor hyperactivity and aggressive behavior. These manifestations were dependent on a permissive action of circulating glucocorticoids and not related to the degree of viral replication in the brain. Hyperthermia and HPA axis activation were also specifically dependent on HSV-1-induced brain IL-1 and PG-E2. The chronic neurological sequel or fatal outcome of HSV-1 encephalitis may be due to viral replication and brain tissue destruction, which are dependent on virus encoded virulence genes. In contrast, the clinical and behavioral signs in the acute phase are a result of activation of neurochemical systems, including cytokines, prostaglandinds and catecholamines. Circulating glucocorticoids play an essential role in mediating the physiologic actions of HSV-1-induced brain products and the clinical syndrome of encephalitis.

Effect of Mycoplasma fermentans on brain PGE(2): role of glucocorticoids and their receptors.

OBJECTIVES: Mycoplasmas are a group of eubacteria, which cause various diseases in animals and in humans, and can contribute to diseases produced by other infectious agents, particularly HIV. We have recently reported that intracerebral administration of Mycoplasma fermentans (MF) produces both neuroendocrine and behavioral alterations. Some of these responses were mediated by MF-induced production of prostaglandin E(2 )(PGE(2)). The aim of this study was to examine the role of glucocorticoids (GC) in regulating MF-induced brain prostaglandin production. METHODS: Male rats were injected intracerebroventricularly with various doses of heat-inactivated MF, LPS or IL-1 beta and the following parameters were measured: (1) ex vivo production of hippocampal PGE(2), (2) serum levels of ACTH and corticosterone, and (3) binding capacity of [(3)H]-dexamethasone (DEX) to hippocampal cytosol. RESULTS: MF caused a small increase in hippocampal PGE(2) production, but higher doses failed to produce a further increase. In contrast, the effects of LPS or IL-1 beta on PGE(2) were dose-dependent. Removal of circulating GC by bilateral adrenalectomy significantly enhanced MF-induced brain PGE(2) production. The three immune stimulators increased serum levels of ACTH and corticosterone to the same extent. Finally, MF, but not IL-1 beta increased the specific binding of [(3)H]-DEX to hippocampal cytosol. CONCLUSIONS: Brain PGE(2) induced by MF is regulated by endogenous GC. These hormones have an attenuating effect on PGE(2 )production, probably through an MF-induced increase in GC binding by brain tissue. This mechanism may be important in the pathological effect of MF within the brain of AIDS patients.

A novel permissive role for glucocorticoids in induction of febrile and behavioral signs of experimental herpes simplex virus encephalitis.

Herpes simplex virus type 1 (HSV-1) encephalitis may present with fever and behavioral changes, to the extent of a psychotic state and psychomotor agitation. We developed a clinically relevant experimental model of HSV-1 encephalitis and investigated host brain responses associated with its clinical signs and whether these responses depend on the presence of circulating glucocorticoids. Intracerebral inoculation of HSV-1 in rats induced fever, motor hyperactivity and aggressive behavior. In adrenalectomized rats HSV-1 failed to induce these signs, although mortality rate was identical to sham-operated rats. Hypophysectomy or blocking glucocorticoid receptors also prevented HSV-1-induced fever. Dexamethasone replacement therapy to adrenalectomized rats restored the HSV-1-induced fever and behavioral abnormalities. HSV-1 inoculation produced hyperproduction of prostaglandin E(2) by brain slices. This effect was abolished in adrenalectomized rats and was restored by dexamethasone treatment. In intact rats HSV-1 induced brain interleukin-1beta (IL-1beta) gene expression. Adrenalectomy alone caused brain IL-1beta expression, which did not increase after HSV-1 infection. Similarly, HSV-1 induced IL-1beta expression in astrocyte cultures. Removal of cortisol from the culture medium caused basal IL-1beta mRNA expression which was not increased by infection. In conclusion, fever, motor hyperactivity and aggressive behavior during experimental HSV-1 encephalitis are dependent on brain responses, including prostaglandin E(2) and IL-1beta synthesis. Circulating glucocorticoids play an essential permissive role in the induction of these host brain responses.

Acute effects of purified and UV-inactivated Herpes simplex virus type 1 on the hypothalamo-pituitary-adrenocortical axis.

UNLABELLED: Herpes simplex virus type 1 (HSV-1) is a common cause of viral encephalitis, manifested by neuroendocrine and behavioral changes. We have previously demonstrated that HSV-1 induces marked hypothalamo-pituitary-adrenocortical (HPA) axis activation. In this study we characterized the acute effects of HSV-1 on the HPA axis occurring before viral replication and appearance of clinical signs of encephalitis. Since in previous studies we used crude virus preparations which may contain immune factors produced by the infected cells, we tested here the effects of purified HSV-1 virions. HSV-1 was propagated on Vero cells and virions were purified by centrifugation in sucrose gradients. Inactivation of viral infectivity was achieved by UV-irradiation, which caused a million-fold decrease in virus titer, as determined by plaque assay. Intracerebroventricular (ICV) inoculation of crude or purified virions induced a dose dependent increase in serum corticosterone and corticotropin (ACTH). This effect was maximal within 3.5 h postinfection and lasted for 72 h. ICV inoculation of UV-inactivated purified virions caused a marked increase in serum corticosterone and ACTH at 3.5 h, but in contrast to the effect of the active virus, the hormone levels gradually decreased at 24 h, and returned to basal levels at 72 h postinfection. HSV-1-induced HPA axis activation at 3.5 h was completely abolished by pretreatment with interleukin-1 receptor antagonist, injected ICV. Adrenalectomized rats failed to respond to ICV inoculation of purified HSV-1 by increase in ACTH. In contrast, these rats responded to ICV injection of LPS. IN CONCLUSION: (1) HSV-1 can acutely activate the HPA axis before and independently of any viral replication; (2) HSV-1-induced HPA axis activation depends on a permissive action of circulating glucocorticoids and on host derived brain interleukin-1.

Electrical stimulation of the dorsal hippocampus caused a long lasting inhibition of ACTH and adrenocortical responses to photic stimuli in freely moving rats.

The effect of a single train of electrical hippocampal stimulation on ACTH and corticosterone (CS) responses to subsequent photic stimulation was studied in freely moving male rats. The hippocampal stimulation inhibited the stress-induced rise [corrected] in serum CS levels up to 150 h when compared to sham stimulated animals. This effect did not exist at 300 h following stimulation. This sustained hippocampal inhibitory effect on the adrenocortical response, which was not reported previously, was partially abolished by section of the dorsal fornix. The present data demonstrate that dorsal hippocampal stimulation has a long lasting inhibitory effect on pituitary adrenocortical secretion following neural stimuli and this is partially mediated by the dorsal fornix.

Evaluation of the effect of stress on the blood--brain barrier: critical role of the brain perfusion time.

The Gulf war syndrome has drawn increased attention in the issue of the effect of stress on the blood-brain barrier (BBB). We have applied various stressful modalities and tested BBB disruption as measured by the amount of Evans blue (EB) retained by brain parenchyma. We have evaluated the retention of this marker as a function of the perfusion time of the brain following stress. This was done to distinguish between the marker retained in the lumen of small blood vessels and the marker retained by the brain parenchyma. Mice were exposed to either short swim stress or restraint stress. In mice exposed to either swim or restraint stress that were perfused for 1 min, the amount of EB retained in the brain was significantly higher as compared to non-stressed controls. Fifteen min perfusion markedly reduced the EB brain content to levels found in the non-stressed animals. In rats exposed to neural or metabolic stressful stimuli and perfused for 15 min, the EB content was similar to non-stressed controls. Our results demonstrate that various stress modalities have no effect on the BBB permeability and insufficient wash of blood vessels by perfusion may cause misinterpretation of permeability studies.

Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents.

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNFalpha and IL-1beta mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.

Effects of adrenalectomy and corticosterone replacement on the hypothalamic-pituitary response to neural stimuli.

In this study we examined whether circulating glucocorticoids (GC) have a permissive facilitatory role in the hypothalamo-pituitary-adrenal (HPA) axis responses to neural or metabolic stimuli. In control sham operated rats the exposure to photic or acoustic neural stimuli and to either cytoglucopenia induced by 2-deoxyglucose (2-DG) or to hypoglycemia induced by insulin caused a significant 5-fold increase in serum ACTH as compared to basal non-stress levels. In adrenalectomized (Adex) rats tested under basal conditions at 4, 7 and 14 days post-Adex, serum ACTH gradually increased in a time-dependent manner, Also, at 4 days post-Adex the median eminence (ME) content of CRH-41 was markedly depleted but gradually recovered to control levels at 7 and 14 days post-Adex. The serum ACTH responses to both photic and acoustic stimuli tested at the same time points were completely inhibited. In contrast, administration of either insulin or 2-DG caused a marked increase in serum ACTH levels. In Adex rats, implanted with low corticosterone (CS) pellets which produced basal serum levels of CS, ME CRH-41 levels and serum ACTH were similar to control sham operated animals. Exposure to both neural stimuli resulted in a significant depletion in CRH-41 ME content and in a rise in serum ACTH as in the respective controls. On the other hand in rats implanted with high CS pellets which produced stress typical CS serum levels, the ME CRH-41 and serum ACTH responses to both stimuli were markedly inhibited. These results suggest that (1) the HPA axis responses to neural stimuli but not to metabolic stimuli require the presence of circulating GC (2), the lack of ACTH response to neural stimuli in Adex rats may not be related to the low CRH-41 ME content.

Effects of adrenergic and serotonergic agonists in the amygdala on the hypothalamo-pituitary-adrenocortical axis.

The effect of direct administration of adrenergic and serotonergic (5-HT) agonists into the central nucleus of the amygdala (AMG) on the hypothalamo-pituitary-adrenal (HPA) axis have been studied in intact male rats and in animals with 6-hydroxydopamine (6-OHDA) or 5, 7-dihydroxytryptamine (5,7-DHT) neurotoxic lesions in the paraventricular nucleus of the hypothalamus (PVN). In intact animals, the administration of phenylephrine, an alpha1 adrenergic agonist or 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) a 5-HT(1A) agonist caused depletion of median eminence corticotropin releasing hormone and a rise in serum adrenocorticotrophic hormone (ACTH) and corticosterone (CS) levels. Isoproterenol a beta agonist was more effective than phenylephrine and a 5-HT(1B) agonist CP-93, 129 was less effective than 8-OH-DPAT on the adrenocortical activity. The 6-OHDA or 5,7-DHT hypothalamic lesions prevented the stimulatory effects of phenylephrine and 8-OH-DPAT, respectively, which where injected into the AMG, on serum ACTH and CS levels. In view of our previous studies on the effects of the adrenergic and 5-HT antagonists in the AMG and the present data, it is suggested that norepinephrine and 5-HT play an important role in the stimulatory effect of the AMG on the HPA axis. These effects depend on the presence of these excitatory neurotransmitters in the PVN.

Effects of sex hormones on experimental autoimmune myasthenia gravis.

To examine whether exacerbation of myasthenia gravis (MG) can be induced by changes in sex hormone levels we immunized 20 female Lewis rats with torpedo antigen to induce experimental autoimmune MG (EAMG). Ten of the animals underwent surgical ovariectomy prior to the induction of EAMG and 10 served as controls. Anti-acetylcholine receptor antibody (AChR-ab) titres and the degree of decrement on repetitive stimulation electromyography (REMG) at 3 Hz were obtained at base line and compared between rats with and without ovariectomy and a second control group of naïve rats. Three rats in each group were then injected with excess oestrogen and progesterone for one week, and three of the remaining rats in each group were given sham injections, and the degree of decrement on REMG and AchR-ab titres were re-evaluated. Immune reactivity of peripheral lymphocytes and splenic lymphocytes from all groups and controls was also determined. A comparable number of animals with and without ovariectomy developed clinical and electromyographic EAMG. The extent of decrement on REMG and AChR-ab titres did not change following hormonal replacement. Lymphocyte reactivity was similar for rats with and without ovariectomy. In conclusion, sex hormones do not appear to have an influence on the susceptibility to and the severity of MG.

Activation of the adrenocortical axis by surgical stress: involvement of central norepinephrine and interleukin-1.

In the present study, we examined the mechanisms involved in the activation of the adrenocortical axis following surgical stress. Adult male rats underwent surgical laparotomy or craniotomy under ether anesthesia while control rats were only ether-anesthetized. Four hours following laparotomy or craniotomy, serum adrenocorticotropin (ACTH) and corticosterone (CS) were significantly increased and returned to almost basal levels after 24 h. Laparotomy also caused a significant depletion of corticotropin-releasing hormone (CRH-41) in the median eminence (ME). Pretreatment with dexamethasone 50 microg/kg completely abolished the pituitary-adrenal response while pretreatment with type II corticosteroid receptor antagonist caused a significant hypersecretion of both ACTH and CS and inhibited the effect of dexamethasone. The response to laparotomy was markedly attenuated in rats injected with 6-hydroxydopamine into the paraventricular nucleus (PVN) which significantly depletes norepinephrine (NE) PVN content. Intracerebroventricular injection of interleukin-1 receptor antagonist (IL-1ra) also inhibited the pituitary-adrenal response to laparotomy. The results suggest that (1) surgical stress activates the hypothalamo-pituitary-adrenal (HPA) axis via a mechanism which involves the release of CRH from the ME and NE input to the PVN; (2) the adrenocortical response is sensitive to the negative feedback of glucocorticoids via the mediation of type II glucocorticoid receptors, and (3) central IL-1 may be a mediator in the HPA axis response to surgical stress.

Illness, cytokines, and depression.

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.