Increased sensitivity to the locomotor-activating effects of corticotropin-releasing hormone in cholestatic rats

Background & Aims: Fatigue is a common complaint of patients with cholestatic liver disease. Defective central corticotropin-releasing hormone (CRH) release has been postulated as playing a role in the genesis of fatigue and decreased hypothalamic CRH expression has been identified in an animal model of cholestatic liver injury. Therefore, we hypothesized that reduced central CRH release contributes to fatigue associated with cholestatic liver disease and tested this hypothesis in cholestatic rats. Methods: Locomotor activity during prolonged observation, measured by using an infrared beam activity monitor, was used as a surrogate marker of fatigue or fatigability. Rats with cholestasis secondary to bile duct resection (BDR) had significantly lower basal locomotor activity compared with sham controls. Results. Intracerebroventricular injections of CRH (0.05, 0.1, 1.0 mug/rat) caused significantly greater locomotor activation in BDR animals than controls. In BDR rats, this locomotor activation was blocked by the coadministration of the nonspecific CRH-receptor antagonist astressin (25 mug/rat) and the specific CRH type 1-receptor antagonist NBI-27941 (10 mug/rat). Immunoblotting showed a dramatic Increase in hypothalamic CRH type 1-receptor expression in BDR rats compared with controls, which was paralleled by a striking reduction in hypothalamic CRH levels. Conclusions: These findings are consistent with defective central CRH neurotransmission contributing to decreased locomotor activity in cholestatic rats and have direct implications for cholestasis-associated fatigue.