5-HT6 receptor antagonism reduces defecation in rat: A potential treatment strategy for irritable bowel syndrome with diarrhea

Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.