Activation of 5-HT3 receptors in the rat and mouse intestinal tract:: a comparative study

1 This study provides a comprehensive evaluation of 5-HT3 receptor functional distribution in both the rat and mouse intestinal tract. 2 5-HT3A-S receptor splice variant mRNA was expressed throughout the intestine of the rat and mouse; the 5-HT3A-L variant being more common in the rat. 3 5-HT, m-CPB, 1-PBG and 2-methyl-5-hydroxytryptamine (2m5-HT) induced contraction in the jejunum, ileum, proximal colon and distal colon of the rat (pEC(50) range: 2m5-HT, 5.86 +/- 0.40 to m-CPB, 7.47 +/- 0.27) and mouse (pEC(50) range: 1-PBG, 5.34 +/- 0.06 to m-CPB, 6.49 +/- 0.14) in the presence of nontarget 5-HT receptor antagonists, methysergide ( 1 mu M) and GR125487 (0.1 mu M). The rank orders of potency in the four regions of the rat and mouse intestine were concordant with the accepted order and the responses to 5-HT were inhibited by ondansetron ( 0.1 mu M). 4 5-HT3-induced contractions to 5-HT were reduced by tetrodotoxin ( 1 mu M). Pargyline ( 10 mu M) and fluoxetine (1 mu M) potentiated responses in the rat jejunum. Atropine ( 0.1 mu M) potentiated 5-HT3-induced responses in the rat jejunum (E-max 49 - 65%), but attenuated responses in most other regions of the rat and mouse ( e. g. mouse ileum: E-max 57-26%). In the rat jejunum, L- NAME ( 100 mu M) mimicked the effect of atropine, hexamethonium ( 100 mu M) suppressed 5-HT3-induced responses, but tachykinin receptor antagonists were without effect. 5 It is concluded that functional 5-HT3 receptors are present in nerves along the length of the rat and mouse intestinal tract. The mouse proximal colon was found to discriminate 5-HT3 receptor agonist profiles better than any other region in the rat or mouse. The rat jejunum shows evidence of 5-HT uptake and inactivation processes as well as inhibitory nitrergic and nontachykinin excitatory pathways associated with the 5-HT3-induced response.