Sickness behaviors'' such as lethargy, fatigue, and malaise occur commonly in patients with cholestatic liver diseases and contribute significantly to the morbidity associated with these diseases. However, the cause of these symptoms is unknown. Interleukin-1 (IL-1) released within the brain has been implicated in the genesis of a number of ''sickness behaviors,'' including malaise and lethargy. Therefore, we investigated whether experimental cholestatic liver disease caused by bile duct resection (BDR) in rats is associated with enhanced central sensitivity to IL-1-induced ''sickness behaviors.'' The central infusion of IL-1 at a dose that produced an insignificant decrease in locomotor activity in control rats produced a striking reduction in locomotor activity in cholestatic rats. The anorectic response to central IL-1 infusion was similar in cholestatic and noncholestatic animals and did not parallel our locomotor activity findings. Therefore, cholestatic liver injury is characterized by augmented central responsiveness to IL-1 with respect to a decrease in locomotor activity. These findings may explain, at least in part, the high incidence of symptoms such as fatigue, malaise, and lethargy that occur in cholestatic patients and may open novel future avenues for their treatment. (HEPATOLOGY 1998;28:1561-1565.)
Illness can be associated with a number of systemic complaints such as fatigue, malaise, lethargy, weakness, anorexia, loss of social interest, and an inability to concentrate. These symptoms have been termed ''sickness behaviors.'' 1 These symptoms, even when profound, are often overlooked or ignored in the treatment of disease as a result of their nonspecific nature and the lack of specific therapies. They are generally felt to be secondary to the disease process that causes them and that becomes the target of therapeutic endeavors. However, recent evidence suggests that ''sickness behaviors'' are part of a specific and organized response to
Methods
Animal Model. Male Sprague-Dawley rats weighing 200 to 250 g were obtained from Charles River (Pointe Claire, Quebec, Canada). All animals were housed in a light-controlled room maintained at 22°C with a 12-hour day/night cycle and were given free access to food and water. The rats were handled regularly to avoid handling stress during experiments. All animals were treated humanely under University of Calgary Animal Care Committee guidelines.
The model of obstructive cholestasis used was the wellcharacterized model caused by bile duct resection (BDR). To do this, laparotomy was performed under halothane anesthesia, and the bile Abbreviations: IL-1, interleukin-1; BDR, bile duct resection; icv, intracerebroventricular(ly) CRH, corticotropin-releasing hormone; PGE 2 , prostaglandin E