COMBINED BLOCKADE OF 5-HT3-SEROTONIN AND 5-HT4-SEROTONIN RECEPTORS INHIBITS COLONIC FUNCTIONS IN CONSCIOUS RATS AND MICE

We have already reported that 5-hydroxytryptamine(3) (5-HT3) receptor antagonists failed to modify 5-HT-accelerated colonic transit in consc ious rats, but the 5-HT3 and 5-HT4 receptor dual antagonist FK1052 pre vented the enhancement. In this study, the inhibitory effect on the st imulated colonic transit was not also observed with 5-HT4 receptor ant agonists (SDZ205-557 and SB204070) in freely moving rats with chronic cannulas implanted into the proximal colon. In contrast, combined anta gonism by simultaneous administration of ondansetron and the 5-HT4 rec eptor antagonist exerted a drastic inhibitory effect on the propulsive motility. Furthermore, we examined the effect of 5-HT receptor antago nists on 5-HT-induced fluid secretion in mice. Although none of these selective 5-HT receptor antagonists (YM060 and ondansetron as 5-HT3 re ceptor antagonist, SB204070 as 5-HT4 receptor antagonist) by itself pr oduced a great inhibition of the 5-HT-induced diarrhea, the combinatio n of a 5-HT3 receptor antagonist and a 5-HT4 receptor antagonist marke dly reduced the diarrhea. These data suggest that 5-HT-accelerated col onic motility and 5-HT-evoked fluid secretion are mediated by both 5-H T3 and 5-HT4 receptors and that the pathways activated by these recept ors may collaborate.