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      Glucocorticoid Resistance following Herpes Simplex-1 Infection: Role of Hippocampal Glucocorticoid Receptors

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          Herpes simplex-1 (HSV-1) is a sporadic cause of viral encephalitis. We have previously demonstrated that corneal HSV inoculation markedly activates the hypothalamo-pituitary-adrenal (HPA) axis. This activation depends on host derived brain interleukine-1 and was resistant to pretreatment with dexamethasone (dex), possibly because immune factors such as pro-inflammatory cytokines can modify the binding capacity of glucocorticoids in the hippocampus. In the present study, we examined whether resistance of the HPA axis activation following intracerebral HSV-1 infection to dex-induced suppression is associated with modifications in hippocampal or pituitary glucocorticoids (GC) receptors or GC receptors in cultured astrocytes. Male rats were injected intracerebroventricularly with purified HSV-1 or vehicle. 48 h later, dex or vehicle was injected intraperitoneally. Rats were sacrificed 3.5 h later. ACTH and corticosterone (CS) were measured in the serum. Specific binding of <sup>3</sup>H-dex was measured in the cytosolic fraction of the hippocampus and the pituitary. Dex failed to reduce ACTH and CS responses to HSV-1 infection. In contrast, dex significantly reduced ACTH and CS responses to acoustic neural stimuli. Infection with HSV-1 markedly reduced the hippocampal maximal specific binding of dex with no effect on the dissociation constant (K<sub>d</sub>) values. HSV-1 had no effect on the binding of dex in the pituitary. Infection of cultured astrocytes with HSV-1 also reduced the maximal specific binding of dex, but increased the K<sub>d </sub>value. The results suggest that HSV-1 induced GC resistance may be mediated by downregulation of GC receptors in hippocampal tissue. These results may clarify a mechanism responsible for GC resistance following immune challenges.

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          When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.

          Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.
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            The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis.

            There is considerable, although not entirely consistent, evidence that the hippocampus inhibits most aspects of HPA activity, including basal (circadian nadir) and circadian peak secretion as well as the onset and termination of responses to stress. Although much of the evidence for these effects rests only on the measurement of corticosteroids, recent lesion and implant studies indicate that the hippocampus regulates adrenocortical activity at the hypothalamic level, via the expression and secretion of ACTH secretagogues. Such inhibition results largely from the mediation of corticosteroid feedback, although more work is required to determine whether the hippocampus supplies a tonic inhibitory input in the absence of corticosteroids. It must be noted that the hippocampus is not the only feedback site in the adrenocortical system, since removal of its input only reduces, but does not abolish, the efficacy of corticosteroid inhibition, and since other elements of the axis appear eventually to compensate for deficits in feedback regulation. The importance of other feedback sites is further suggested not only by the presence of corticosteroid receptors in other parts of the brain and pituitary, but also by the improved prediction of CRF levels by combined hypothalamic and hippocampal receptor occupancy. The likelihood of feedback mediated by nonhippocampal sites underscores the need for future work to characterize hippocampal influence on HPA activity in the absence of changes in corticosteroid secretion. However, despite the fact that the hippocampus is not the only feedback site, it is distinguished from most potential feedback sites, including the hypothalamus and pituitary, by its high content of both type I and II corticosteroid receptors. The hippocampus is therefore capable of mediating inhibition over a wide range of steroid levels. The low end of this range is represented by corticosteroid inhibition of basal (circadian nadir) HPA activity. The apparent type I receptor specificity of this inhibition and the elevation of trough corticosteroid levels after hippocampal damage support a role for hippocampal type I receptors in regulating basal HPA activity. It is possible that basal activity is controlled in part through hippocampal inhibition of vasopressin, since the inhibition of portal blood vasopressin correlates with lower levels of hippocampal receptor occupancy, and the expression of vasopressin by some CRF neurons is sensitive to very low corticosteroid levels. At the high end of the physiological range, stress-induced or circadian peak corticosteroid secretion correlates strongly with occupancy of the lower affinity hippocampal type II receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Endotoxin produces a depressive-like episode in rats.

               Raz Yirmiya (1996)
              Activation of the immune system produces psychological and physiological effects, which resemble the characteristics of depression. The present study was designed to investigate further, in rats, the similarity between the behavioral effects of immune activation and a model of depression in animals. Reduction in the preference for and consumption of saccharin solutions and suppression of sexual behavior were used as models of one essential feature of depression, the inability to experience pleasure (anhedonia). Other measures testing this model were the reduction in food consumption, body weight, locomotor activity, and social interaction. It was found that systemic injection of lipopolysaccharide (endotoxin), which is a potent activator of the immune system, significantly decreased saccharin preference in fluid-deprived rats. Lipopolysaccharide (LPS) also decreased free consumption of saccharin, but not water, in non-deprived rats. Several indices of male sexual behavior were significantly suppressed following LPS administration. Chronic, but not acute, treatment with the tricyclic antidepressant imipramine abolished the suppressive effect of LPS on saccharin preference. Moreover, chronic, but not acute, treatment with imipramine also reduced and facilitated the recovery from the suppressive effects of LPS on food consumption, body weight, social interaction and activity in the open-field test. The results suggest that activation of the immune system in rats produces anhedonia and other depressive-like symptoms, which can be attenuated or completely blocked by chronic treatment with an antidepressant drug.

                Author and article information

                S. Karger AG
                July 2007
                16 May 2007
                : 85
                : 4
                : 207-215
                aDepartment of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical School, and bDepartment of Psychology, Hebrew University, Jerusalem, Israel
                102976 Neuroendocrinology 2007;85:207–215
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 46, Pages: 9
                CRF, Adrenocorticotropin, Adrenal Steroids and Stress


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