Fatigue of cholestasis and the serotoninergic neurotransmitter system in the rat

Abstract

Fatigue associated with cholestasis may impair health-related quality of life. The pathogenesis of this symptom is largely unknown, but it has been suggested that central serotoninergic neurotransmission may be implicated and that serotonin 1A receptor agonists may yield improvement. The aim of this study was to study the central serotoninergic system, specifically the serotonin (5-HT) 1A receptor-mediated pathway of serotoninergic neurotransmission, in a bile duct resection rat model of cholestasis. Fatigue was assessed in the forced swim test in sham and bile duct-resected rats. The serotonin behavioral syndrome, which includes hyperlocomotion, was assessed in both groups of rats after escalating doses of the 5-HT 1A receptor agonist 8-hydroxy(di-n-propylamine)tetralin (8-OH DPAT). 5-HT 1A and 5-HT 2 receptor densities were explored in four brain regions using a receptor-binding assay. Extracellular 5-HT and 5-hydroxyindoleacetic acid were measured via in vivo brain dialysis. Bile duct-resected rats spent more time floating in the forced swim test, and 8-OH DPAT decreased floating time in cholestatic rats (P < .01). Dose-response curves created with 8-OH DPAT for the serotonin behavioral syndrome were similar in bile duct-resected and sham-operated rats. 5-HT 1A and 5-HT 2 receptor densities in most brain regions and extracellular serotonin levels were similar in both groups of rats. In conclusion, 5-HT 1A receptor agonist-induced amelioration of fatigue in cholestatic rats may be nonspecific and not linked to reversal of the pathophysiology of fatigue associated with cholestasis; however, these data do not exclude a potential role of the central serotoninergic system in the evolution of fatigue. (HEPATOLOGY 2005;41:731-737.)

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

“…Therefore, increased serotonin release within the hypothalamus (in the areas where 5‐HT 3 receptors are expressed) may contribute to decreased hypothalamic 5‐HT 3 receptor expression in cholestatic rats. Consistent with this hypothesis, we and others 6 have identified biochemical evidence of increased hypothalamic serotonin turnover in BDR vs sham rats, as reflected by increased hypothalamic 5‐HIAA to 5‐HT ratios. Interestingly, it appears that 5‐HT 3 receptor activity within the CNS becomes more evident in the setting of enhanced serotonin release 40 .…”

“…Moreover, the ratio of hypothalamic 5‐HIAA to 5‐HT levels was significantly elevated (Fig. 4C) in BDR compared to sham rats, consistent with increased hypothalamic serotonin turnover in BDR vs sham rats 6 …”

5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats

“…As we used sham-operated rats as controls in our behavioral experiments, our data exclude the probability of other factors (like various mediators released during post-operative period) causing the state of being adynamic, supporting that our neurochemical findings occur as a consequence of cholestasis. Supportingly, the cholestatis developed overtly in 7 days and performing experiments with BDR rats 7 days following resection is also consistent with other studies using this model (Ç elik et al, 2005;Swain et al, 1993).…”

Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats

“…Bile duct ligation (BDL) is extensively used as a model of acute and chronic liver injury accompanied by cholestasis [1,2,3,4]. Obstructive jaundice occurs immediately and evolves to cirrhosis in four to six weeks [5,6].…”