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Coates, Matthew D.

Anatomy and Neurobiology

2005

PhD

Serotonin (5-HT) plays a critical role in the regulation of gastrointestinal (GI) function. When secreted by enterochromaffin (EC) cells residing in the GI mucosa, 5-HT initiates peristalsis, secretion and sensory signaling in the gut by acting on receptors of intrinsic and extrinsic primary afferent neurons that project to the lamina propria. The serotonin-selective reuptake transporter (SERT), which is expressed on intestinal enterocytes, terminates the actions of 5-HT by removing it from the interstitial space. This cycle must remain intact for precise control of the reflexes described above. Alterations in the components of 5-HT availability (biosynthesis, mucosal content and release, or uptake) may contribute to motor, sensory and secretory disorders in the gut. 5-HT may play a significant role in the development of symptoms in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), GI disorders associated with dysmotility and altered pain sensation. Previous studies of the EC cell numbers and 5-HT mucosal content in humans suggest 5-HT availability may be altered in IBD and IBS. The work associated with this dissertation was designed to elucidate the features mucosal 5-HT signaling system in the mammalian gut and to determine whether or not elements of 5-HT signaling are altered in disorders such as IBD and IBS, and whether these changes could contribute to altered gut function and sensation. The first study in this dissertation investigated elements of intestinal 5-HT signaling in the gut of the guinea pig to provide a broader view of how 5-HT prevalence and release varies, if at all, among different regions of the GI tract. In this study, it was demonstrated that EC cell density, 5-HT content and 5-HT release levels decrease progressively in an aboral direction along the guinea pig intestinal tract.
The second study evaluated whether intestinal 5-HT availability (as measured by EC cell density, 5-HT content, biosynthetic capacity, SERT prevalence, and 5-HT release) is altered in IBD and/or IBS. This study demonstrated that individuals with IBD and IBS exhibit reduced levels of SERT, 5-HT synthetic capacity, and 5-HT content in their colonic mucosa without any evidence of a change in 5-HT release levels. This led us to the hypothesis that increased 5-HT availability in IBD and IBS due to a reduction in 5-HT transport capacity could contribute to altered gut motility and sensitivity, which are features of these disorders. The final study reported here tested the latter hypothesis by comparing the gastrointestinal motility and visceral sensitivity of mice exposed to a daily IP injection of paroxetine (a selective serotonin reuptake inhibitor) or its vehicle. It was determined that inhibition of serotonin transport reduces motility, as demonstrated by decreased small intestinal transit and fecal output, and attenuates the visceromotor response in mice. This provided evidence that conditions which induce a relative serotonin transport blockade can lead to alterations in motility and bowel habits as well as changes in visceral sensitivity that mimic those found in IBD or IBS. These findings show that 5-HT signaling characteristics vary among different regions of the mammalian intestinal tract. In addition, IBD and IBS were found to be associated with alterations in key aspects of this signaling process, including a decrease in the prevalence of the major uptake protein SERT. It was shown that blockade of SERT function could lead to changes in bowel function that mimic those found in IBD and IBS. This work provides evidence that changes in 5-HT signaling can lead to GI dysfunction.