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THE 5HT-4 RECEPTOR AGONIST PRUCALOPRIDE STIMULATES ILEAL MUCOSAL GROWTH IN THE MOUSE
Christine Park*, Sarah Armenia, Lucy Zhang, Robert A. Cowles
Surgery, Yale University, New Haven, CT

Introduction:
Enteric serotonin influences intestinal homeostasis with recent findings suggesting its function as a mucosal growth factor. Previously, our lab has shown that genetic knockout of the serotonin reuptake transporter (SERT) in mice is associated with significant increases in crypt cell proliferation and intestinal mucosal surface area. Further, treatment with selective serotonin reuptake inhibitors caused de-novo intestinal mucosal growth with the most pronounced effect found in the distal small bowel. While an indirect, acetylcholine-mediated mechanism has been postulated to explain these effects of knock-out or blockade of SERT, a direct effect of 5-HT on enterocytes remains plausible. Since the 5HT-4 receptor has been documented to be present on enterocytes, the effect of prucalopride, a 5-HT4 receptor agonist was evaluated in this study. We hypothesized that treatment with a 5HT-4 specific agonist, prucalopride, would lead to increased intestinal mucosal growth in the murine small intestine.

Material and Methods:
Following institutional approval, 8-12 week old wild-type C57Bl/6 mice were treated parenterally with prucalopride (5 mg/kg) for 2 weeks. The drug was delivered by surgically implanted subcutaneous mini-osmotic pumps. Control animals received phosphate buffered saline (PBS) by the same method. At the end of the treatment period, proximal, middle and distal small bowel were harvested and H&E stained histologic sections were examined for morphologic parameters.

Results:
Prucalopride treatment caused no recognizable adverse events and prucalopride-treated mice exhibited similar weight gain when compared to mice treated with PBS. Villus height (VH) and crypt depth (CD) were both significantly increased in the distal small bowel of mice treated with prucalopride compared with mice treated with PBS. In the proximal and middle small bowel, no significant change was seen in VH but CD was increased in both areas in prucalopride-treated animals when compared to animals treated with PBS.

Conclusion:
Parenteral administration of the 5HT-4 receptor specific agonist, prucalopride, results in morphologic changes in the murine small intestine that are most prominent in the distal small bowel. These findings suggest that 5-HT may directly interact with mucosal receptors to induce intestinal mucosal growth. Further study of the role of the 5-HT4 signaling pathway and the effects of 5-HT4 agonists on mucosal cell proliferation are warranted.


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