The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders

Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT4 partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT3 antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT1 agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders. Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT4 partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT3 antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT1 agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders. Digestive diseases are a prevalent and expensive problem. According to the National Digestive Diseases Information Clearinghouse, they yearly affect 60–70 million people in the United States, cause 13% of all hospitalizations, provoke approximately 50 million physician office visits, and cost about $107 billion (direct + indirect costs). Disorders that involve the enteric innervation affect motility, and while not often lethal, they cause considerable morbidity. Pathogenesis may be infectious, inflammatory, neurological or, as in the case of functional bowel diseases, unknown. These conditions, which include irritable bowel syndrome (IBS), are highly prevalent. In the United States, they affect 25–55 million people, initiate 2.5–3.5 million physician visits per year, and are involved in approximately 20%–40% of all visits to gastroenterologists. Because causative biochemical or anatomical abnormalities of the bowel have not been identified, functional bowel diseases are commonly assumed to be psychogenic; nevertheless, it is conceivable that abnormalities within the gut, in at least a subset of patients, also contribute to their causation. This possibility is supported by the complexity of the intrinsic innervation of the bowel, the enteric nervous system (ENS), and that of the interactions of central and peripheral mechanisms in the control of gastrointestinal motility. The ENS is a center of integrative neuronal activity that is able to regulate the behavior of the gut, even in the absence of input from the CNS, and is engaged in a two-way dialogue with the CNS.1Gershon M.D. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome.J Clin Gastroenterol. 2005; 39: S184-S193Crossref PubMed Scopus (132) Google Scholar The ENS and the CNS thus influence each other. The ENS, moreover, is extremely large, and with regard to its ultrastructural organization and neuronal diversity, more like brain than peripheral nerve. It follows that an adequate understanding of signaling within the bowel and from the bowel to the brain can contribute to the development of improved means of treating and, ultimately preventing functional bowel disease and other disorders of gastrointestinal motility. Because serotonin plays critical roles in enteric neurotransmission, the initiation and propagation of intrinsic enteric reflexes, and in gut-to-brain signaling,1Gershon M.D. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome.J Clin Gastroenterol. 2005; 39: S184-S193Crossref PubMed Scopus (132) Google Scholar it is important to understand serotonin’s contributions to normal and abnormal gastrointestinal function. The physiological role of serotonin has still not been completely elucidated, partly because of the presence of multiple serotonin receptor subtypes in the gut wall and partly because suitable ligands for in vivo studies are lacking. Still, some serotonin receptor agonists and antagonists are now in use for the treatment of functional gastrointestinal disorders and others are under investigation or in development. This review summarizes our current understanding of serotonergic signaling in the gastrointestinal tract and its implications for the pathogenesis and treatment of functional gastrointestinal disorders. It is common in medical jargon to talk about “the serotonin system,” as if such a singular entity actually exists. Serotonin, however, is used for signaling in many diverse systems both in the brain and in the periphery. In the brain, in which serotonin is best known, most serotonergic neurons are located in the nuclei of the median raphe.2Hornung J.P. The human raphe nuclei and the serotonergic system.J Chem Neuroanat. 2003; 26: 331-343Crossref PubMed Scopus (168) Google Scholar These nuclei, however, are functionally diverse; thus, the descending medullary neurons of the raphe obscurus, magnus, and pallidus are quite different from their ascending pontine and mesencephalic counterparts in the raphe pontis, centralis, and dorsalis. The descending projections of raphe nuclei influence spinal and brainstem mechanisms and are very much involved in the central modulation of pain and in pathologic pain syndromes,3Sommer C. Is serotonin hyperalgesic or analgesic?.Curr Pain Headache Rep. 2006; 10: 101-106Crossref PubMed Scopus (32) Google Scholar often, unfortunately, from the bowel. By contrast, the ascending raphe projections are directed toward areas of higher integrative function and are implicated in the regulation of mood, sleep, sex, appetite, and just about everything that makes life worth living.4Barnes N.A. Sharp T. A review of central 5-HT receptors and their function.Neuropsychopharmacology. 1999; 38: 1083-1152Google Scholar, 5Gingrich J.A. Hen R. Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice.Psychopharmacology (Berl). 2001; 155: 1-10Crossref PubMed Scopus (176) Google Scholar Despite the importance and diversity of central serotonergic mechanisms, the brain is not the ne plus ultra of serotonin. The brain actually contains very little serotonin in relative terms.6Erspamer V. Occurrence of indolealkylamines in nature.in: Erspamer V. Handbook of experimental pharmacology: 5-hydroxytryptamine and related indolealkylamines. Vol 19. Springer-Verlag, New York1966: 132-181Google Scholar Most of the body’s serotonin (∼95%) resides in the gut. Within the bowel, serotonin is synthesized by the enterochromaffin (EC) subtype of enteroendocrine cell7Erspamer V. Über den 5-Hydroytryptamin-(Enteramin)Gehalt des Magen-Darmtraktes bei den Wirbelten.Naturwissenschaften. 1953; 40: 318-319Crossref Scopus (4) Google Scholar, 8Erspamer V. Pharmacology of indolealklyamines.Pharmacol Rev. 1954; 6: 425-487PubMed Google Scholar, 9Vialli M. Histology of the enterochromaffin cell system.in: Erspamer V. Handbook of experimental pharmacology: 5-hydroxytryptamine and related indolealkylamines. Vol 19. Springer-Verlag, New York1966: 1-65Google Scholar and by serotonergic neurons of the myenteric plexus.10Gershon M.D. Drakontides A.B. Ross L.L. Serotonin: synthesis and release from the myenteric plexus of the mouse intestine.Science. 1965; 149: 197-199Crossref PubMed Google Scholar, 11Wade P.R. Tamir H. Kirchgessner A.L. Gershon M.D. Analysis of the role of 5-HT in the enteric nervous system using anti-idiotypic antibodies to 5-HT receptors.Am J Physiol. 1994; 266: G403-G416PubMed Google Scholar, 12Gershon M.D. 5-HT (serotonin) physiology and related drugs.Curr Opin Gastroenterol. 2000; 16: 113-120Crossref PubMed Google Scholar, 13Gershon M.D. Review article: serotonin receptors and transporters—roles in normal and abnormal gastrointestinal motility.Aliment Pharmacol Ther. 2004; 20: 3-14Crossref PubMed Google Scholar EC cells contain one form of the rate-limiting enzyme in serotonin’s biosynthesis, tryptophan hydroxylase-1 (TpH-1),14Walther D.J. Peter J.U. Bashammakh S. Hortnagl H. Voits M. Fink H. Bader M. Synthesis of serotonin by a second tryptophan hydroxylase isoform.Science. 2003; 299: 76Crossref PubMed Scopus (630) Google Scholar, 15Cote F. Thevenot E. Fligny C. Fromes Y. Darmon M. Ripoche M.A. Bayard E. Hanoun N. Saurini F. Lechat P. Dandolo L. Hamon M. Mallet J. Vodjdani G. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function.Proc Natl Acad Sci U S A. 2003; 100: 13525-13530Crossref PubMed Scopus (143) Google Scholar whereas enteric and central serotonergic neurons contain another, TpH-2, which is a different gene product.15Cote F. Thevenot E. Fligny C. Fromes Y. Darmon M. Ripoche M.A. Bayard E. Hanoun N. Saurini F. Lechat P. Dandolo L. Hamon M. Mallet J. Vodjdani G. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function.Proc Natl Acad Sci U S A. 2003; 100: 13525-13530Crossref PubMed Scopus (143) Google Scholar EC cells produce and secrete far more serotonin than either central or peripheral serotonergic neurons, such that the serotonin secreted by EC cells overflows to reach the gastrointestinal (GI) lumen16Grønstad K.O. DeMagistris L. Dählström A. Nilsson O. Price B. Zinner M.J. Jaffe B.M. Ahlman H. The effects of vagal nerve stimulation on endoluminal release of serotonin and substance P into the feline small intestine.Scand J Gastroenterol. 1985; 20: 163-169Crossref PubMed Google Scholar, 17Wingren U. Ahlman H. Dahlström A. Enerbäck L. Endoluminal secretin of serotonin and histamine into the small intestine of normal and nematode-infected rats.Biogenic Amines. 1988; 5: 297-306Google Scholar and blood.18Toh C.C. Release of 5-hydroxytryptamine (serotonin) from the dog’s gastrointestinal tract.J Physiol (Lond). 1954; 126: 248-254Google Scholar, 19Tamir H. Payette R.F. Huang Y.L. Liu K.P. Gershon M.D. Human serotonectin: a blood glycoprotein that binds serotonin and is associated with platelets and white blood cells.J Cell Sci. 1985; 73: 187-206PubMed Google Scholar, 20Morrissey J.J. Walker M.N. Lovenberg W. The absence of tryptophan hydroxylase activity in blood platelets.Proc Soc Exp Biol Med. 1977; 154: 496-499Crossref PubMed Google Scholar, 21Chen J.J. Zhishan L. Pan H. Murphy D.L. Tamir H. Koepsell H. Gershon M.D. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter (SERT): abnormal intestinal motility and the expression of cation transporters.J Neurosci. 2001; 21: 6348-6361PubMed Google Scholar Overflowing serotonin from EC cells, which is taken up and concentrated in platelets, is virtually the sole source of blood serotonin; platelets lack TpH and thus cannot produce serotonin on their own. The primary targets of the serotonin that is secreted by EC cells are the mucosal projections of primary afferent neurons. These include extrinsic nerves,22Sugiuar T. Bielefeldt K. Gebhart G.F. TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation.J Neurosci. 2004; 24: 9521-9530Crossref PubMed Scopus (82) Google Scholar, 23Hillsley K. Kirkup A.J. Grundy D. Direct and indirect actions of 5-hydroxytryptamine on the discharge of mesenteric afferent fibers innervating the rat jejunum.J Physiol (Lond). 1998; 506: 551-561Crossref Scopus (107) Google Scholar, 24Hillsley K. Grundy D. Sensitivity to 5-hydroxytryptamine in different afferent subpopulations within mesenteric nerves supplying the rat jejunum.J Physiol (Lond). 1998; 509: 717-727Crossref Scopus (94) Google Scholar, 25Grundy D. Blackshaw L.A. Hillsley K. Role of 5-hydroxytryptamine in gastrointestinal chemosensitivity.Dig Dis Sci. 1994; 39: S44-S47Crossref PubMed Google Scholar, 26Blackshaw L.A. Grundy D. Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret.J Auton Nerv Syst. 1993; 45: 41-50Abstract Full Text PDF PubMed Scopus (111) Google Scholar which transmit sensations of nausea and discomfort to the central nervous system (CNS), and the mucosal projections of intrinsic primary afferent neurons (IPANs); submucosal IPANs initiate peristaltic and secretory reflexes,27Kirchgessner A.L. Tamir H. Gershon M.D. Identification and stimulation by serotonin of intrinsic sensory neurons of the submucosal plexus of the guinea pig gut: activity-induced expression of Fos immunoreactivity.J Neurosci. 1992; 12: 235-249PubMed Google Scholar, 28Kirchgessner A.L. Liu M.-T. Gershon M.D. In situ identification and visualization of neurons that mediate enteric and enteropancreatic reflexes.J Comp Neurol. 1996; 371: 270-286Crossref PubMed Scopus (95) Google Scholar, 29Pan H. Gershon M.D. Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine.J Neurosci. 2000; 20: 3295-3309PubMed Google Scholar, 30Sidhu M. Cooke H.J. Role for 5-HT and ACh in submucosal reflexes mediating colonic secretion.Am J Physiol Gastointest Liver Physiol. 1995; 269: G346-G351PubMed Google Scholar, 31Cooke H.J. Sidhu M. Wang Y.-Z. 5-HT activates neural reflexes regulating secretion in the guinea-pig colon.Neurogastroenterol Motil. 1997; 9: 181-186Crossref PubMed Google Scholar, 32Kim M. Cooke H.J. Javed N.H. Carey H.V. Christofi F. Raybould H.E. D-glucose releases 5-hydroxytryptamine from human BON cells as a model of enterochromaffin cells.Gastroenterology. 2001; 121: 1400-1406Abstract Full Text Full Text PDF PubMed Google Scholar while myenteric IPANs initiate giant migrating contractions.33Nagakura Y. Kiso T. Miyata K. Ito H. Iwaoka K. Yamaguchi T. The effect of the selective 5-HT(3) receptor agonist on ferret gut motility.Life Sci. 2002; 71: 1313-1319Crossref PubMed Scopus (11) Google Scholar, 34Bertrand P.P. Furness J.B. Bornstein J.C. 5-HT and ATP stimulate the mucosal terminals of some myenteric sensory neurons and cause increases in excitability in a population of sensory neurons. Falk Symposium No. 112. Neurogastroenterology—From the Basics to the Clinics. 1999Google Scholar Serotonin secreted by myenteric neurons mediates fast and slow excitatory neurotransmission and is involved in the regulation of GI motility.13Gershon M.D. Review article: serotonin receptors and transporters—roles in normal and abnormal gastrointestinal motility.Aliment Pharmacol Ther. 2004; 20: 3-14Crossref PubMed Google Scholar Clearly, the variety in serotonin-secreting cells may not be kaleidoscopic, but it is impressive and counterproductive to discussions of a unitary serotonin system. Serotonergic cells include ascending and descending raphe neurons, enteric neurons, EC cells, and platelets (plus mast cells in rats and mice6Erspamer V. Occurrence of indolealkylamines in nature.in: Erspamer V. Handbook of experimental pharmacology: 5-hydroxytryptamine and related indolealkylamines. Vol 19. Springer-Verlag, New York1966: 132-181Google Scholar); moreover, the various serotonin-secreting cells have little or nothing to do with one another. They play many different roles in normal physiology and contribute to at least an equal number of pathophysiologies of disease states. The central serotonergic neurons provide inputs to a multiplicity of other neurons throughout much of the CNS and do not function as a unit. Central serotonergic neurons, moreover, are separated from peripheral serotonergic neurons, platelets, and EC cells by the blood-brain barrier, which is impermeable to serotonin. The projections of enteric serotonergic neurons are not thoroughly understood, but they are believed to be descending interneurons that innervate follower cells in both plexuses.13Gershon M.D. Review article: serotonin receptors and transporters—roles in normal and abnormal gastrointestinal motility.Aliment Pharmacol Ther. 2004; 20: 3-14Crossref PubMed Google Scholar, 35Wardell C.F. Bornstein J.C. Furness J.B. Projections of 5-hydroxytryptamine-immunoreactive neurons in guinea-pig distal colon.Cell Tissue Res. 1994; 278: 379-387Crossref PubMed Google Scholar, 36Furness J.B. Costa M. Neurons with 5-hydroxytryptamine-like immunoreactivity in the enteric nervous system: their projections in the guinea pig small intestine.Neuroscience. 1982; 7: 341-350Crossref PubMed Scopus (103) Google Scholar, 37Erde S.M. Sherman D. Gershon M.D. Morphology and serotonergic innervation of physiologically identified cells of the guinea pig’s myenteric plexus.J Neurosci. 1985; 5: 617-633PubMed Google Scholar They do not, however, project to smooth muscle or other effectors. The serotonin secreted by EC cells acts locally in a paracrine fashion,29Pan H. Gershon M.D. Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine.J Neurosci. 2000; 20: 3295-3309PubMed Google Scholar, 38Bülbring E. Crema A. The release of 5-hydroxytryptamine in relation to pressure exerted on the intestinal mucosa.J Physiol (Lond). 1959; 146: 18-28Google Scholar, 39Bertrand P.P. Real-time detection of serotonin release from enterochromaffin cells of the guinea-pig ileum.Neurogastroenterol Motil. 2004; 16: 511-514Crossref PubMed Scopus (43) Google Scholar although the nerves it activates are mostly situated relatively far from them.40Wade P.R. Westfall J.A. Ultrastructure of enterochromaffin cells and associated neural and vascular elements in the mouse duodenum.Cell Tissue Res. 1985; 241: 557-563Crossref PubMed Google Scholar The EC cell-to-nerve junctions thus bear no resemblance to neuromuscular junctions or to any other synapses of the central or peripheral nervous systems (Figure 1). EC cells, like other cells of the GI epithelium, are in motion. They turn over and are replaced by stem cells in the necks of gastric glands and the crypts of Lieberkühn in the small and large intestines.41Roth K.A. Hermiston M.L. Gordon J.I. Use of transgenic mice to infer the biological properties of small intestinal stem cells and to examine the lineage relationships of their descendants.Proc Natl Acad Sci U S A. 1991; 88: 9407-9411Crossref PubMed Google Scholar, 42Stappenbeck T.S. Wong M.H. Saam J.R. Mysorekar I.U. Gordon J.I. Notes from some crypt watchers: regulation of renewal in the mouse intestinal epithelium.Curr Opin Cell Biol. 1998; 10: 702-709Crossref PubMed Scopus (98) Google Scholar, 43Wong M.H. Stappenbeck T.S. Gordon J.I. Living and commuting in intestinal crypts.Gastroenterology. 1999; 116 (comment): 208-210Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar As a result of the movement and transience of EC cells, traditional synapses cannot be found on them (nerves are not good at innervating moving targets),40Wade P.R. Westfall J.A. Ultrastructure of enterochromaffin cells and associated neural and vascular elements in the mouse duodenum.Cell Tissue Res. 1985; 241: 557-563Crossref PubMed Google Scholar and EC cells do not focus the transmitter they release as precisely as do neurons. In fact, the hypersecretion of serotonin by EC cells may have evolved as a compensation for the lack of close connections at EC cell-to-neuron junctions. The local concentration of serotonin in the mucosa is thus quite high,39Bertrand P.P. Real-time detection of serotonin release from enterochromaffin cells of the guinea-pig ileum.Neurogastroenterol Motil. 2004; 16: 511-514Crossref PubMed Scopus (43) Google Scholar which suggests that the functions of mucosal serotonin are unlikely to be limited to stimulating nerves. Serotonin, for example, has been postulated to affect crypt epithelial secretion and proliferation.44Tutton P.J.M. The influence of serotonin on crypt cell proliferation in the jejunum of rat.Virchows Arch B Cell Pathol. 1974; 16: 79-87Crossref PubMed Google Scholar, 45Tutton P.J.M. Barkla D.H. Neural control of colonic cell proliferation.Cancer. 1980; 45: 1172-1177Crossref PubMed Google Scholar, 46Gill R.K. Saksena S. Tyagi S. Alrefai W.A. Malakooti J. Sarwar Z. Turner J.R. Ramaswamy K. Dudeja P.K. Serotonin inhibits Na+/H+ exchange activity via 5-HT4 receptors and activation of PKC α in human intestinal epithelial cells.Gastroenterology. 2005; 128: 962-974Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar The continual secretion of serotonin in mammoth concentrations has necessitated the evolution of effective mechanisms for its inactivation. Receptors for which serotonin is a ligand, like all receptors, desensitize; therefore, serotonin cannot be allowed to linger on them. Responses of the bowel, moreover, while slow, are not so slow that they can depend on unaided diffusion to regulate the timing of their initiation. Enzyme-mediated catabolism of signaling molecules, such as that of acetylcholine (ACh) by acetylcholinesterase, is a well-known mechanism of transmitter inactivation. Serotonin is catabolized by monoamine oxidase47Gershon M.D. Sherman D.L. Pintar J.E. Type-specific localization of monoamine oxidase in the enteric nervous system: relationship to 5-hydroxytryptamine, neuropeptides, and sympathetic nerves.J Comp Neurol. 1990; 301: 191-213Crossref PubMed Google Scholar, 48Molinoff P.B. Axelrod J. Biochemistry of catecholamines.Annu Rev Biochem. 1971; 40: 465-500Crossref PubMed Google Scholar and, in the gut, by transferases and other enzymes49Gershon M.D. Ross L.L. Radioisotopic studies of the binding, exchange, and distribution of 5-hydroxytryptamine synthesized from its radioactive precursor.J Physiol (Lond). 1966; 186: 451-476Google Scholar, 50Airaksinen M.M. Miettinen T.A. Huttunen J. Glucuronidation of 5-hydroxyindole derivatives in vitro.Biochem Pharmacol. 1965; 14: 1019-1023Crossref PubMed Google Scholar, 51Gerber G.B. Deroo J. Mazanowska A. Metabolism of 5-hydroxytryptophan in isolated perfused intestine from normal and x-irradiated rat.Arch Int Physiol Biochim. 1972; 80: 733-739Crossref PubMed Google Scholar; however, because all these enzymes are intracellular molecules, they do not contribute to the termination of serotonin-mediated intercellular signaling events. There is no extracellular enzyme, analogous to acetylcholinesterase, that rapidly catabolizes serotonin. Because serotonin is a base, it is positively charged at a physiologic pH. As a result, serotonin penetrates poorly through the lipid bilayers of plasma membranes. Serotonin inactivation is therefore accomplished mainly by transporter-mediated uptake into either the cells that secrete it or into neighboring cells, which in the mucosa are enterocytes.52Fuller R.W. Wong D.T. Serotonin uptake and serotonin uptake inhibition.Ann N Y Acad Sci. 1990; 600: 68-80Crossref PubMed Google Scholar, 53Iversen L. Neurotransmitter transporters: fruitful targets for CNS drug discovery.Mol Psychiatry. 2000; 5: 357-362Crossref PubMed Google Scholar The serotonin reuptake transporter (SERT; 5-HTT) is the primary molecule responsible for inactivating serotonin in the CNS54Blakely R.D. Berson H.E. Fremeau R.T. Caron M.G. Peek M.M. Prince H.K. Bradley C.C. Cloning and expression of a functional serotonin transporter from rat brain.Nature. 1991; 354: 66-70Crossref PubMed Google Scholar, 55Hoffman B. Mezey E. Brownstein M. Cloning of a serotonin transporter affected by antidepressants.Science. 1991; 254: 579-580Crossref PubMed Google Scholar, 56Ramamoothy S. Bauman A.L. Moore K.R. Han H. Yang-Fen T. Chang A.S. Ganapathy V. Blakely R.D. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.Proc Natl Acad Sci U S A. 1993; 90: 2542-2546Crossref PubMed Google Scholar, 57Chang A.S. Chang S.M. Starnes D.M. Schroeter S. Bauman A.L. Blakely R.D. Cloning and expression of the mouse serotonin transporter.Mol Brain Res. 1996; 43: 185-192Crossref PubMed Scopus (87) Google Scholar, 58Lesch K.-P. Balling U. Gross J. Strauss K. Wolozin B.L. Murphy D.L. Riederer P. Organization of the human serotonin transporter gene.J Neural Transm. 1994; 95: 157-162Crossref PubMed Google Scholar and gut,21Chen J.J. Zhishan L. Pan H. Murphy D.L. Tamir H. Koepsell H. Gershon M.D. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter (SERT): abnormal intestinal motility and the expression of cation transporters.J Neurosci. 2001; 21: 6348-6361PubMed Google Scholar, 59Wade P.R. Chen J. Jaffe B. Kassem I.S. Blakely R.D. Gershon M.D. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract.J Neurosci. 1996; 16: 2352-2364PubMed Google Scholar, 60Chen J.-X. Pan H. Rothman T.P. Wade P.R. Gershon M.D. Guinea pig 5-HT transporter: cloning, expression, distribution and function in intestinal sensory reception.Am J Physiol. 1998; 275: G433-G448PubMed Google Scholar, 61Martel F. Recent advances on the importance of the serotonin transporter SERT in the rat intestine.Pharmacol Res. 2006; 54: 73-76Crossref PubMed Scopus (21) Google Scholar but, when SERT is inhibited or knocked out, organic cation transporters and the dopamine transporter provide backups of lower affinity but high capacity.21Chen J.J. Zhishan L. Pan H. Murphy D.L. Tamir H. Koepsell H. Gershon M.D. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter (SERT): abnormal intestinal motility and the expression of cation transporters.J Neurosci. 2001; 21: 6348-6361PubMed Google Scholar Because SERT is the target of antidepressants and cocaine, the existence of the backup transporters is highly significant. These molecules compensate for the loss of SERT function; however, the degree of compensation is not sufficient to maintain normal function. Mice that lack SERT exhibit increased colonic motility and increased water in stools and display an alternating pattern of diarrhea and constipation.21Chen J.J. Zhishan L. Pan H. Murphy D.L. Tamir H. Koepsell H. Gershon M.D. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter (SERT): abnormal intestinal motility and the expression of cation transporters.J Neurosci. 2001; 21: 6348-6361PubMed Google Scholar Transcription of SERT, furthermore, is decreased as a consequence of experimental inflammation of the bowel62Linden D.R. Chen J.X. Gershon M.D. Sharkey K.A. Mawe G.M. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G207-G216Crossref PubMed Google Scholar and is also decreased in patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS).63Coates M.D. Mahoney C.R. Linden D.R. Sampson J.E. Chen J.J. Blaszyk H. Crowell M.D. Sharkey K.A. Gershon M.D. Mawe G.M. Moses P.L. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and IBS.Gastroentrology. 2004; 126: 1657-1664Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar In those conditions, the behavior of the gut is not dissimilar to that of the bowel of mice that lack SERT. For this reason, SERT knockout mice may be considered to be a possible animal model of IBS. Of course, it is not possible to interview mice to ascertain whether the cy