Serotonin and the 5-HT2B receptor in the development of enteric neurons

We tested the hypothesis that 5-HT promotes the differentiation of enteric neurons by stimulating a developmentally regulated receptor expressed by cr est-derived neuronal progenitors. 5-HT and the 5-HT2 agonist (6)-2,5-dimeth oxy-4-iodoamphetamine. HCl (DOI) enhanced in vitro differentiation of enter ic neurons, both in dissociated cultures of mixed cells and in cultures of crest-derived cells isolated from the gut by immunoselection with antibodie s to p75(NTR). The promotion of in vitro neuronal differentiation by 5-HT a nd DOI was blocked by the 5-HT1/2 antagonist methysergide, the pan-5-HT2 an tagonist ritanserin, and the 5-HT2B/2C-selective antagonist SB206553. The 5 -HT2A-selective antagonist ketanserin did not completely block the developm ental effects of 5-HT. 5-HT induced the nuclear translocation of mitogen-ac tivated protein kinase. This effect was blocked by ritanserin. mRNA encodin g 5-HT2A and 5-HT2B receptors was detected in the fetal bowel (stomach and small and large intestine), but that encoding the 5-HT2C receptor was not. mRNA encoding the 5-HT2B receptor and 5-HT2B immunoreactivity were found to be abundant in primordial [embryonic day 15 (E15)-E16] but not in mature m yenteric ganglia. 5-HT2B-immunoreactive cells were found to be a subset of cells that expressed the neuronal marker PGP9.5. These data demonstrate for the first time that the 5-HT2B receptor is expressed in the small intestin e as well as the stomach and that it is expressed by enteric neurons as wel l as by muscle. It is possible that by stimulating 5-HT2B receptors, 5-HT a ffects the fate of the large subset of enteric neurons that arises after th e development of endogenous sources of 5-HT.