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Altered Neuroimmunoendocrine Communication during a Condition of Chronically Increased Brain Corticotropin-Releasing Hormone Drivea

Authors

  • JOHANNES M. H. M. REUL,

    Corresponding author
    1. Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Section Neuroimmunoendocrinology, Kraepelinstrasse 2, D-80804 Munich, Germany
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  • MARTA S. LABEUR,

    1. Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Section Neuroimmunoendocrinology, Kraepelinstrasse 2, D-80804 Munich, Germany
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  • G. JAN WIEGERS,

    1. Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Section Neuroimmunoendocrinology, Kraepelinstrasse 2, D-80804 Munich, Germany
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  • ASTRID C. E. LINTHORST

    1. Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Section Neuroimmunoendocrinology, Kraepelinstrasse 2, D-80804 Munich, Germany
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  • a

    These studies were supported by the Volkswagen Stiftung (Grants I/68 430 and I/70 543).

Address for correspondence: J. M. H. M. Reul, Ph.D., Max Planck Institute of Psychiatry, Clinical Institute, Department of Neuroendocrinology, Section Neuroimmunoendocrinology, Kraepelinstrasse 2, D-80804 Munich, Germany; Telephone: 49 89 30622 443; Fax: 49 89 30622 371; e-mail: reul@mpipsykl.mpg.de

Abstract

Abstract: Presently, it is clear that the brain, immune system, and endocrine system build a complex network of interactions at various levels. Inflammation, which may be regarded as a stressful challenge, initiates apart from immunological, autonomic, and neuroendocrine responses also profound behavioral (e.g., immobility, social disinterest) changes. Key mediators herein are corticotropin-releasing hormone (CRH) and cytokines, such as interleukin-1β (IL-1β). Currently, the behavioral changes, collectively termed sickness behavior, are thought to be adaptive responses to support the body's efforts to fight the infection. Using in vivo microdialysis and biotelemetry in freely moving animals, we have studied the monoaminergic circuits in the brain implicated in the regulation of physiological and behavioral responses to a peripheral inflammatory challenge (see also chapter of Linthorst and Reul in this volume). To expand our insight into the relationship between hypersecretion of CRH and physiological and behavioral abnormalities associated with stress-related disorders, a series of experiments was conducted with long-term centrally CRH-infused rats. These rats showed reduced body weight gain, decreased food intake, elevated plasma ACTH and corticosterone levels, thymus involution and immunosuppression, but, paradoxically, enhanced IL-1β mRNA expression in spleen macrophages. After a peripheral endotoxic challenge on the seventh day of treatment, the CRH-infused rats produced aberrant (i.e., blunted and/or delayed) HPA axis, fever, behavioral, and hippocampal serotonergic responses. However, endotoxin-induced plasma IL-1 and IL-6 bioactivities were significantly enhanced in these animals. The data show that chronically elevated central CRH levels as occurring during chronic stress result in defective central nervous system and immune system responses to an acute (inflammatory) challenge. These observations provide evidence that chronic CRH hypersecretion is an important factor in the etiology of stress-related disorders.

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