Nonspecific systemic complaints are commonly encountered in patients with cholestatic liver diseases. However, the cause of these symptoms is poorly understood. Because corticotropin-releasing hormone (CRH) has been implicated as a mediator of sickness-related systemic symptoms, we examined CRH-mediated neuroendocrine and behavioral responses in rats with cholestasis due to bile duct resection (BDR) or sham resected (sham) controls. BDR and sham rats were placed individually in an open field apparatus, and the number of inner and outer squares entered, as well as the number of fecal boli produced, counted over a 5-minute period. Fecal boli production and inner squares entered are dependent on central CRH release. BDR and sham rats entered the same number of outer squares; however, BDR rats entered significantly fewer inner squares and produced fewer fecal boli than did sham rats, suggesting defective central CRH release in BDR rats. Immediately after exposure to the open field, rats were killed and blood adrenocorticotropic hormone (ACTH) levels measured. ACTH release is dependent on central CRH release. BDR rats demonstrated significantly lower plasma ACTH levels after exposure to an open field than did sham animals. To further explore the central CRH defect in BDR rats, hypothalamic CRH contents were determined in BDR and sham rats with and without exposure to restraint stress. BDR rats had significantly lower basal hypothalamic CRH levels than sham animals, and CRH levels did not further decrease in BDR rats with restraint stress (as normally occurs). These results are consistent with defective CRH-mediated responses in cholestatic rats.(ABSTRACT TRUNCATED AT 250 WORDS)