Combined blockade of 5-HT₃- and 5-HT₄-serotonin receptors inhibits colonic functions in conscious rats and mice

We have already reported that 5-hydroxytryptamine₃ (5-HT₃) receptor antagonists failed to modify 5-HT-accelerated colonic transit in conscious rats, but the 5-HT₃ and 5-HT₄ receptor dual antagonist FK1052 prevented the enhancement. In this study, the inhibitory effect on the stimulated colonic transit was not also observed with 5-HT₄ receptor antagonists (SDZ205-557 and SB204070) in freely moving rats with chronic cannulas implanted into the proximal colon. In contrast, combined antagonism by simultaneous administration of ondansetron and the 5-HT₄ receptor antagonist exerted a drastic inhibitory effect on the propulsive motility. Furthermore, we examined the effect of 5-HT receptor antagonists on 5-HT-induced fluid secretion in mice. Although none of these selective 5-HT receptor antagonists (YM060 and ondansetron as 5-HT₃ receptor antagonist, SB204070 as 5-HT₄ receptor antagonist) by itself produced a great inhibition of the 5-HT- induced diarrhea, the combination of a 5-HT₃ receptor antagonist and a 5- HT₄ receptor antagonist markedly reduced the diarrhea. These data suggest that 5-HT-accelerated colonic motility and 5-HT-evoked fluid secretion are mediated by both 5-HT₃ and 5-HT₄ receptors and that the pathways activated by these receptors may collaborate.