Central fatigue commonly occurs in patients with primary biliary cirrhosis (PBC) and correlates closely with depression, and cholestatic rats exhibit central fatigue. Therefore, we undertook a series of experiments in both rats with cholestasis caused by bile duct resection (BDR) and sham-resected controls (15 days after surgery) to determine if experimental cholestasis is associated with symptoms of depression that can be modeled in rats, namely anhedonia (loss of pleasure) and the loss of social interest. BDR rats exhibited significant anhedonia compared with sham controls as indicated by a loss in their preference for consuming a saccharin solution, a highly desirable drink for rats. Furthermore, social interest was examined by determining the time BDR or sham rats spent investigating a juvenile rat in an open-field apparatus compared with the time spent on nonsocial behaviors. BDR rats exhibited significantly reduced time spent in social investigation and significantly more time in nonsocial behaviors than did sham rats. Major depression in humans is often associated with elevated circulating glucocorticoid levels and impaired glucocorticoid feedback. Therefore, we measured these parameters in BDR and sham rats and found a striking elevation in circulating glucocorticoid levels in BDR compared with sham animals. However, elevated circulating glucocorticoid levels in BDR rats suppressed normally in response to exogenous dexamethasone, indicating intact glucocorticoid feedback control at the pituitary level in BDR rats. In summary, we have identified behaviors in cholestatic rats that are consistent with those seen in depression. (HEPATOLOGY 1998;28:6-10.)
Fatigue is a common complaint in patients with chronic liver disease. Moreover, patients with the cholestatic liver disease, primary biliary cirrhosis (PBC), often present only with fatigue, even early in the course of their disease. In fact, in an epidemiological survey of PBC patients in Canada, fatigue occurred in up to 80% of patients. 1 Furthermore, fatigue impacted adversely on job performance and family life in 30% and 57% of patients with PBC, respectively. 1 Despite this high prevalence of fatigue and its adverse effect on the quality of life in patients with PBC, the etiology of fatigue is not understood. Furthermore, given the subjective nature of fatigue, little research activity is currently under way in an effort to better understand fatigue in the context of liver disease. We have recently described a novel model of central fatigue assessment in rats. 2 Using this model, we have identified significant central fatigue that occurs in rats with cholestatic, but not acute, hepatocellular experimental liver disease. 2 Furthermore, we have found that activation of central 5HT 1A receptors ameliorates fatigue in cholestatic rats, supporting the hypothesis that fatigue results from a disruption in central neural pathways in cholestasis. 2 Interestingly, central fatigue has been found to correlate strongly with symptoms of depression. Specifically, in two recent studies in patients with PBC, fatigue and depression were highly correlated. 3,4 Furthermore, depression occurs in up to 75% of patients with the chronic fatigue syndrome. 5 Therefore, a close relationship between depression and central fatigue appears to exist. Depression is a complex psychiatric syndrome that is very difficult to study in rats in that not all of the symptoms of depression can be modeled in rats. Specifically, symptoms that require a subjective verbal report would be excluded. 6,7 Two core symptoms are of central importance in the diagnosis of major depression (DSM-III-R): loss of interest or pleasure (anhedonia) and depressed mood. Loss of social interest and anhedonia can be modeled in rats. In the early 1980s, Katz identified that rats receiving a variety of chronic unpredictable stressors developed, over a period of weeks, a loss of interest in consuming saccharin or sucrose when added to their drinking water. 8 This finding suggested that chronic stress in these animals resulted in the development of an anhedonic deficit, because sweet-tasting solutions are normally highly appealing to rats. [6][7][8] Further studies have demonstrated that this finding is highly reproducible and is reversible by the administration of antidepressant drugs. [6][7][8]10 Furthermore, the Flinders sensitive rat strain that has been bred as an animal model of endogenous depression is exquisitely sensitive to the anhedonia-inducing effects of chronic mild stress when compared with control Flinders resistant rats. 9,11 Therefore, this model of anhedonia induction has become widely used as a good model for the study of endogenous depression. Given that chronic stress has been postulated as contributing to the genesis of endogenous depression in humans, 6,7,12 and that chronic cholestasis may be regarded as a chronic stress, findings in rats may be of significant clinical relevance with respect to depression in cholestasis.