LONG-TERM INTRACEREBROVENTRICULAR INFUSION OF CORTICOTROPIN-RELEASINGHORMONE ALTERS NEUROENDOCRINE NEUROCHEMICAL, AUTONOMIC, BEHAVIORAL, AND CYTOKINE RESPONSES TO A SYSTEMIC INFLAMMATORY CHALLENGE

Corticotropin-releasing hormone (CRH) was infused intracerebroventricu larly into rats for 7 d via a miniosmotic pump (1 mu g .mu l(-1). hr(- 1)). Body temperature and locomotor activity were recorded during the treatment using biotelemetry, whereas hippocampal serotonergic neurotr ansmission and free corticosterone levels were monitored using in vivo microdialysis on day 7 of CRH treatment. During the microdialysis exp eriment, behavioral activity was scored by assessing the time during w hich rats were active (locomotion, grooming, eating, drinking). Contin uous intracerebroventricular infusion of CRH produced a transient incr ease in body temperature and locomotion. Moreover, intracerebroventric ularly CRH-treated rats showed elevated free corticosterone levels wit h no apparent diurnal rhythm. Intraperitoneal administration of bacter ial endotoxin [lipopolysaccharide (LPS); 100 mu g/kg body weight] on d ay 7 of CRH/vehicle treatment produced a marked fever response in cont rol animals, which was significantly blunted in intracerebroventricula rly CRH-treated rats. Although free corticosterone levels reached simi lar peak concentrations in both intracerebroventricularly vehicle- and CRH-infused groups after LPS, this response was delayed significantly by similar to 1 hr in the intracerebroventricularly CRH-treated anima ls. Microdialysis experiments showed no changes in basal extracellular levels of serotonin and 5-hydroxyindoleacetic acid in intracerebroven tricularly CRH-infused animals. Injection of LPS in intracerebroventri cularly CRH-treated rats produced a blunted 5-HT response and a delaye d onset of behavioral inhibition and other signs of sickness behavior. Assessment of the endotoxin-induced cytokine responses showed signifi cantly 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 lev els produce marked changes in basal (largely CRH regulated) physiologi cal and behavioral processes accompanied by aberrant responses to an a cute challenge. The present study provides evidence that chronic CRH h ypersecretion is an important factor in the etiology of stress-related disorders.