title: 5-Hydroxytryptophan activates colonic myenteric neurons and propulsive motor function through 5-HT4 receptors in conscious mice.
abstract: Serotonin [5-hydroxytryptamine (5-HT)] acts as a modulator of colonic motility and secretion. We characterized the action of the 5-HT precursor 5-hydroxytryptophan (5-HTP) on colonic myenteric neurons and propulsive motor activity in conscious mice. Fos immunoreactivity (IR), used as a marker of neuronal activation, was monitored in longitudinal muscle/myenteric plexus whole mount preparations of the distal colon 90 min after an intraperitoneal injection of 5-HTP. Double staining of Fos IR with peripheral choline acetyltransferase (pChAT) IR or NADPH-diaphorase activity was performed. The injection of 5-HTP (0.5, 1, 5, or 10 mg/kg ip) increased fecal pellet output and fluid content in a dose-related manner, with a peak response observed within the first 15 min postinjection. 5-HTP (0.5-10 mg/kg) dose dependently increased Fos expression in myenteric neurons, with a maximal response of 9.9 +/- 1.0 cells/ganglion [P < 0.05 vs. vehicle-treated mice (2.3 +/- 0.6 cells/ganglion)]. There was a positive correlation between Fos expression and fecal output. Of Fos-positive ganglionic cells, 40 +/- 4% were also pChAT positive and 21 +/- 5% were NADPH-diaphorase positive in response to 5-HTP, respectively. 5-HTP-induced defecation and Fos expression were completely prevented by pretreatment with the selective 5-HT4 antagonist RS-39604. These results show that 5-HTP injected peripherally increases Fos expression in different populations of cholinergic and nitrergic myenteric neurons in the distal colon and stimulates propulsive colonic motor function through 5-HT4 receptors in conscious mice. These findings suggest an important role of activation of colonic myenteric neurons in the 5-HT4 receptor-mediated colonic propulsive motor response.
authors.affiliation: Digestive Diseases Research Center and Center for Neurovisceral Sciences and Woman's Health, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA. lixinw@ucla.edu
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: V
authors.initials: V
authors.lastname: Martínez
authors.forename: H
authors.initials: H
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Taché
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003106:Colon / Q000294:innervation*; D003672:Defecation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects / Q000502:physiology*
chemical_list: D044422:Receptors, Serotonin, 5-HT4; D006916:5-Hydroxytryptophan; D009252:NADPH Dehydrogenase; D002795:Choline O-Acetyltransferase