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Volume 17, Number 11,
Issue of June 1, 1997
pp. 4448-4460
Copyright ©1997 Society for Neuroscience
Long-Term Intracerebroventricular Infusion of
Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical,
Autonomic, Behavioral, and Cytokine Responses to a Systemic
Inflammatory Challenge
Received Feb. 5, 1997; revised March 12, 1997; accepted March 21, 1997.
Astrid C. E. Linthorst1,
Cornelia Flachskamm1,
Stephen J. Hopkins2,
Margaret E. Hoadley2,
Marta
S. Labeur1,
Florian Holsboer1, and
Johannes M. H. M. Reul1
1 Max Planck Institute of Psychiatry, Clinical
Institute, Department of Neuroendocrinology, Section
Neuroimmunoendocrinology, 80804 Munich, Germany, and
2 University of Manchester Rheumatic Diseases Centre,
Clinical Sciences Building, Hope Hospital, Salford M6 8HD, United
Kingdom
Corticotropin-releasing hormone (CRH) was infused
intracerebroventricularly into rats for 7 d via a miniosmotic pump
(1 µg · µl 1 · hr1). Body
temperature and locomotor activity were recorded during the treatment
using biotelemetry, whereas hippocampal serotonergic neurotransmission
and free corticosterone levels were monitored using in
vivo microdialysis on day 7 of CRH treatment. During the
microdialysis experiment, behavioral activity was scored by assessing
the time during which rats were active (locomotion, grooming, eating,
drinking). Continuous intracerebroventricular infusion of CRH produced
a transient increase in body temperature and locomotion. Moreover,
intracerebroventricularly CRH-treated rats showed elevated free
corticosterone levels with no apparent diurnal rhythm.
Intraperitoneal administration of bacterial endotoxin
[lipopolysaccharide (LPS); 100 µg/kg body weight] on day 7 of
CRH/vehicle treatment produced a marked fever response in control
animals, which was significantly blunted in intracerebroventricularly
CRH-treated rats. Although free corticosterone levels reached similar
peak concentrations in both intracerebroventricularly vehicle- and CRH-infused groups after LPS, this response was delayed significantly by ~1 hr in the intracerebroventricularly CRH-treated animals. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in
intracerebroventricularly CRH-infused animals. Injection of LPS in
intracerebroventricularly CRH-treated rats produced a blunted 5-HT
response and a delayed onset of behavioral inhibition and other signs
of sickness behavior. Assessment of the endotoxin-induced cytokine
responses showed significantly enhanced plasma interleukin-1 (IL-1) and
IL-6 bioactivities in the intracerebroventricularly CRH-infused animals
3 hr after injection of LPS, whereas tumor necrosis factor bioactivity
responses were not different.
Our data demonstrate that chronically elevated brain CRH levels produce
marked changes in basal (largely CRH regulated) physiological and
behavioral processes accompanied by aberrant responses to an acute
challenge. The present study provides evidence that chronic CRH
hypersecretion is an important factor in the etiology of stress-related disorders.
Key words:
corticotropin-releasing hormone;
endotoxin;
hypothalamic-pituitary-adrenocortical axis;
corticosterone;
body
temperature;
sickness behavior;
locomotion;
serotonin;
hippocampus;
interleukin-1;
interleukin-6;
in vivo microdialysis;
biotelemetry;
rat
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