| These studies describe mechanisms by which peripheral serotonin (5-HT) reduces food intake in rats. Experiments compared mechanisms recruited by 5-HT to those of a model satiety system mediated by cholecystokinin (CCK). Initial studies examined whether stimulation of CCK-A receptors was required for anorexia following systemic 5-HT. Pretreatment of animals with the CCK-A receptor antagonist, devazepide, blocked CCK-stimulated anorexia but did not alter 5-HT-induced reductions in food intake. These studies demonstrated that mechanisms recruited by 5-HT, unlike CCK, were independent of CCK-A receptor stimulation. Additional studies examined whether an intact abdominal vagus nerve was required to elicit anorexia following peripherally-administered 5-HT. After vagotomy, CCK-mediated anorexia was blocked, but in the same animals, the effect of 5-HT on food intake was unaltered. Thus, unlike, CCK, peripheral 5-HT reduced food intake by vagally-independent mechanisms. The surgeries were verified immunohistochemically using anti-neurofilament protein to stain axons. Final studies considered the actions of 5-HT on the pylorus as one gastric site where 5-HT might act to alter feeding. These studies characterized the pharmacological profile for 5-HT-induced contraction of the pylorus in vitro. The complete response-curve for 5-HT-induced contraction of the pylorus was generated using a classical smooth muscle assay. Antagonist studies revealed that the 5-HT-stimulated contraction was blocked by diltiazem, ketanserin, xylamidine, and methysergide, but was insensitive to tetrodotoxin, ICS 205-930, prazosin, devazepide, and ({dollar}-{dollar})pindolol pretreatment. Thus, it was inferred that a 5-HT{dollar}sb{lcub}rm 2-type{rcub}{dollar} receptor, located on smooth muscle, mediated contraction to 5-HT in rat pylorus. The pharmacology of 5-HT-induced contraction of the pylorus agrees with in vivo studies demonstrating a peripheral 5-HT{dollar}sb2{dollar} receptor mechanism mediating the anorectic action of peripheral 5-HT in rats. This correlation justifies further functional studies examining the pylorus as a site where peripheral 5-HT might alter feeding in rats. Overall, this thesis defines peripheral mechanisms for 5-HT control of feeding by dissociating its actions from those of CCK, providing the basis for future investigations of the sites of action of peripheral 5-HT in controlling ingestive behavior. |
