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The Journal of Neuroscience, August 15, 2001, 21(16):6348-6361

Maintenance of Serotonin in the Intestinal Mucosa and Ganglia of Mice that Lack the High-Affinity Serotonin Transporter: Abnormal Intestinal Motility and the Expression of Cation Transporters

Jason J. Chen¹, Zhishan Li¹, Hui Pan¹, Dennis L. Murphy², Hadassah Tamir^{1, 3}, Hermann Koepsell⁴, and Michael D. Gershon¹

¹ Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, ² Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892, ³ New York State Psychiatric Institute, New York, New York 10032, and ⁴ Anatomisches Institut der Bayerischen Julius-Maximilians-Universitat, D-97070 Würzburg, Germany

The enteric serotonin reuptake transporter (SERT) has been proposed to play a critical role in serotonergic neurotransmission and in the initiation of peristaltic and secretory reflexes. We analyzed potential compensatory mechanisms and enteric function in the bowels of mice with a targeted deletion of SERT. The guts of these animals were found to lack mRNA encoding SERT; moreover, high-affinity uptake of 5-HT into epithelial cells, mast cells, and enteric neurons was present in the SERT +/+ bowel but absent in the SERT / bowel. However, both the SERT +/+ gut and the / gut expressed molecules capable of transporting 5-HT, but with affinities and selectivity much lower than those of SERT. These included the dopamine transporter (DAT) and polyspecific organic cation transporters OCT-1 and OCT-3. DAT and OCT immunoreactivities were present in both the submucosal and myenteric plexuses, and the OCTs were also located in the mucosal epithelium. 5-HT was found in all of its normal sites in the SERT / bowel, which contained mRNA encoding tryptophan hydroxylase, but no 5-HT was present in the blood of SERT / animals. Stool water and colon motility were increased in most SERT / animals; however, the increase in motility (diarrhea) occasionally alternated irregularly with decreased motility (constipation). The watery diarrhea is probably attributable to the potentiation of serotonergic signaling in SERT / mice, whereas the transient constipation may be caused by episodes of enhanced 5-HT release leading to 5-HT receptor desensitization.

Key words: serotonin reuptake transporter; enteric nervous system; gastrointestinal motility; organic cation transporters; dopamine transporter; SERT knock-out mice

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21166348-14$05.00/0

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