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Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin

Authors

  • Astrid C. E. Linthorst,

    1. Max Planck Institute of Psychiatry, Section Neuropsychopharmacology, Kraepelinstrasse 2-10, D-80804 Munich, Germany
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    • *

      These authors contributed equally to this study.

  • Sharada Karanth,

    1. Max Planck Institute of Psychiatry, Section Neuropsychopharmacology, Kraepelinstrasse 2-10, D-80804 Munich, Germany
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      These authors contributed equally to this study.

  • Nicholas Barden,

    1. Neuroscience Research Section, CHUL Research Centre and Department of Physiology, Laval University, Ste-Foy, Quebec, Canada G1 V 4G2
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  • Florian Holsboer,

    1. Max Planck Institute of Psychiatry, Section Neuropsychopharmacology, Kraepelinstrasse 2-10, D-80804 Munich, Germany
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  • Johannes M. H. M. Reul

    1. Max Planck Institute of Psychiatry, Section Neuropsychopharmacology, Kraepelinstrasse 2-10, D-80804 Munich, Germany
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J. M. H. M. Reul, as above. E-mail: reul@mpipsykl.mpg.de

Abstract

The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 μg/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1β and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-α levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration.

 It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.

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