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Downregulated hypothalamic 5‐HT 3 receptor expression and enhanced 5‐HT 3 receptor antagonist‐mediated improvement in fatigue‐like behaviour in cholestatic rats
Author(s) -
Nguyen H.,
Wang H.,
Le T.,
Ho W.,
Sharkey K. A.,
Swain M. G.
Publication year - 2008
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/j.1365-2982.2007.01016.x
Subject(s) - tropisetron , endocrinology , medicine , 5 ht receptor , serotonin , receptor antagonist , receptor , cholestasis , neurotransmitter , antagonist , 5 ht3 receptor , receptor expression , chemistry
Abstract The serotonin neurotransmitter system, including the 5‐HT 3 receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5‐HT 3 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‐HT 3 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‐hydroxyindoleacetic 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‐HT 3 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‐HT 3 receptor expression, and enhanced sensitivity to locomotor activation induced by 5‐HT 3 receptor antagonism, thereby implicating the 5‐HT 3 receptor system in cholestasis associated fatigue.