RT Journal Article SR Electronic T1 Long-Term Intracerebroventricular Infusion of Corticotropin-Releasing Hormone Alters Neuroendocrine, Neurochemical, Autonomic, Behavioral, and Cytokine Responses to a Systemic Inflammatory Challenge JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 4448 OP 4460 DO 10.1523/JNEUROSCI.17-11-04448.1997 VO 17 IS 11 A1 Astrid C. E. Linthorst A1 Cornelia Flachskamm A1 Stephen J. Hopkins A1 Margaret E. Hoadley A1 Marta S. Labeur A1 Florian Holsboer A1 Johannes M. H. M. Reul YR 1997 UL http://www.jneurosci.org/content/17/11/4448.abstract AB Corticotropin-releasing hormone (CRH) was infused intracerebroventricularly into rats for 7 d via a miniosmotic pump (1 μg · μl−1 · hr−1). 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.