Ligand-induced 5-HT3 receptor internalization in enteric neurons in rat ileum.
OBJECTIVE
Release of 5-hydroxytryptamine (5-HT) from mucosal enterochromaffin cells and activation of 5-HT(3) receptors (5-HT(3)Rs) on neurons in the gut wall is important in the response of the gut to the luminal environment. Intestinal inflammation is associated with increased levels of mucosal 5-HT. The aims of the study were to determine the following: (1) if 5-HT(3)R undergoes ligand-induced internalization in myenteric neurons, and (2) the effect of long-term increase of mucosal 5-HT on 5-HT(3)Rs.


METHODS
Acute effects of exogenous 5-HT or endogenous release of 5-HT by luminal glucose on cellular localization of 5-HT(3)Rs was determined by immunohistochemistry and confocal microscopy. Treatment with the serotonin re-uptake inhibitor, fluoxetine, for 6 days (20 mg/kg daily orally) was used to increase mucosal 5-HT chronically in rats. Net ileal fluid movement was measured in anesthetized rats by the weight change of a 2.5% agarose cylinder.


RESULTS
Acute increases in 5-HT induced by exogenous or endogenous 5-HT decreased 5-HT(3)R immunoreactivity at the neuronal cell membrane by 70% and 60%, respectively. Chronic fluoxetine treatment increased mucosal levels of 5-HT and decreased membrane 5-HT(3)R immunoreactivity by 27%. Net fluid absorption was decreased by a 5-HT(3)R agonist or by luminal glucose; this was attenuated 88% and 99%, respectively, by fluoxetine treatment.


CONCLUSIONS
Long-term increase in 5-HT in the intestinal mucosa results in increased 5-HT(3)R internalization in myenteric neurons. Chronic changes in mucosal 5-HT may alter gastrointestinal secretory and motor function via ongoing loss of receptor from neuronal membrane, causing a mismatch between luminal content and absorption.
Freeman
Samara L
SL
Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, 95616, USA.
Glatzle
Jorg
J
Robin
Carla S
CS
Valdellon
Melissa
M
Sternini
Catia
C
Sharp
James W
JW
Raybould
Helen E
HE
D000818:Animals; D015153:Blotting, Western; D005473:Fluoxetine / Q000494:pharmacology; D007082:Ileum / Q000294:innervation / Q000378:metabolism; D007150:Immunohistochemistry; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D005473:Fluoxetine; D017294:Ondansetron; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors