Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats

The serotonin neurotransmitter system, including the 5-HT3 receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT3 receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT3 receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxy-indoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT3 receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT3 receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT3 receptor antagonism, thereby implicating the 5-HT3 receptor system in cholestasis associated fatigue.