Fatigue is a common complaint in patients with liver disease; however, the etiology of fatigue is poorly understood and no therapeutic options are available to treat it. Altered central neurotransmission, especially serotonergic, appears to play a role in the genesis of fatigue. In this study, we describe a rat model of fatigue assessment using a swim tank, and we used this model to document the degree of fatigue in rat models of cholestasis caused by bile duct resection (BDR) and of hepatitis caused by carbon tetrachloride (CCl4) administration. Fatigue was quantitated as the time spent floating and struggling over a 15-minute period after placement in the swim tank, and an overall activity score was calculated. Using this technique, BDR rats exhibited significantly enhanced floating times and an overall reduction in activity score compared with noncholestatic controls (P < or = .01). On the other hand, CCl4-treated rats showed a marked variability in floating and struggling times and activity scores such that, overall, CCl4-treated rats were not significantly different from normal controls. Therefore, we used BDR and noncholestatic control rats to examine the effects of a serotonin (5HT1A) receptor agonist (LY293284) on cholestasis-associated fatigue. BDR rats treated with LY293284 (0.3 mg/kg subcutaneously 24, 5, and 1 hour before placement in the swim tank) showed marked reductions in floating times and an increase in overall activity scores compared with BDR controls (P < or = .001). LY293284 was without effect in noncholestatic animals. These results suggest that fatigue can be quantitated in rat models of liver disease and that 5HT1A receptor agonists may provide a useful therapeutic tool in the treatment of cholestatic liver disease-associated fatigue.