Résumé
The serotonergic system plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, serotonin has been implicated in the control of motility and visceral pain associated with irritable bowel syndrome (IBS). Here, we investigated the impact of blocking differently activated conformational states of the type 6 serotonin receptor (5-HT
) upon intestinal motility and diarrhea in both non-stressed and stressed mice. We evaluated full and partial inverse agonists (SB-399885 and PZ-1444, respectively), which target constitutively active serotonin 5-HT
receptors and a neutral antagonist (CPPQ), which targets agonist-activated serotonin 5-HT
receptors. We found that both inverse agonists and the neutral antagonist, administered intraperitoneally at the same doses similarly reduce defecation in physiological and stressful conditions. The effect of PZ-1444 was significantly potentiated by the co-administration of either SB-399885 or CPPQ. CPPQ co-administration did not attenuate the effect of SB-399885 and this combination did not produce significantly stronger inhibition of defecation than SB-399885 administered alone. Combining PZ-1444 and CPPQ produced the most pronounced effect on defecation. The present findings confirm the contribution of both constitutively active and agonist-stimulated serotonin 5-HT
receptors to intestinal motility and diarrhea and highlights the serotonin 5-HT
receptor as a promising drug target for the treatment of functional GI disorders.