5-HT (serotonin) physiology and related drugs

Current Opinion in Gastroenterology

Volumn 16, Issue 2, 2000, Pages 113-120

  Gershon, Michael D ^a  

^a College of Physicians and Surgeons ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000670006     PISSN: 02671379     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001574-200003000-00004     Document Type: Article

References (88)

1. Bayliss WM, Starling EH: The movements and innervation of the small intestine. J Physiol (Lond) 1899, 24:99-143.
2. Bayliss WM, Starling EH: The movements and innervation of the small intestine. J Physiol (Lond) 1900, 26:125-138.
3. Bayliss WM, Starling EH: The movements and innervation of the large intestine. J Physiol (Lond) 1900, 26:107-118.
4. Auerbach L: About a plexus myenteric, a previously unknown neuroganglionic apparatus in the colon of vertebrates (in German). Vorläufige Mitteilung. vol Breslau: E. Morgenstern, 1862.
5. Auerbach L: Preliminary report about neural apparatus of the colon (in German). Arch Pathol Anat Physiol 1864, 30:457-460.
6. Meissner G: About the nerves of the colon wall (in German). Z Ration Med 1857, 8:364-366.
7. Langley JN: The Autonomic Nervous System, Part 1. Cambridge, UK: W. Heffer; 1921.
8. Trendelenburg P: Physiological and pharmacological experiments concerning the peristalsis of the small intestine (in German). Naunyn-Schmiedebergs Arch Exp. Pathol Pharmakol 1917, 81:55-129.
9. Furness JB, Costa M: The Enteric Nervous System. New York: Churchill Livingstone; 1987.
10. Gershon MD, Kirchgessner AL, Wade PR: Functional anatomy of the enteric nervous system. In: Johnson LR, Alpers DH, Jacobson ED, Walsh JH, eds. Physiology of the Gastrointestinal Tract. Third Edition, vol 1. New York: Raven Press; 1994:381-422.
11. Bülbring E, Lin RCY: The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis, the local production of 5-hydroxytryptamine and its release in relation to intraluminal pressure and propulsive activity. J Physiol (Lond) 1958, 140:381-407.
12. Bülbring E, Crema A: Observations concerning the action of 5-hydroxytryptamine on the peristaltic reflex. Br J Pharmacol 1958, 13:444-457.
13. Kosterlitz HW, Lees GM: Pharmacological analysis of intrinsic intestinal reflexes. Pharmacol Rev 1964, 16:301-339.
14. Bülbring E, Lin RCY, Schofield G: An investigation of the peristaltic reflex in relation to anatomical observations. Q J Exp Physiol 1958, 43:26-37.
15. Bülbring E, Crema A: The action of 5-hydroxytryptamine, 5-hydroxytryptophan and reserpine on intestinal peristalsis in anaesthetized guinea-pigs. J Physiol (Lond) 1959, 146:29-53.
16. Bülbring E, Crema A: The release of 5-hydroxytryptamine in relation to pressure exerted on the intestinal mucosa. J Physiol (Lond) 1959, 146:18-28.
17. Boullin DJ: Observations on the significance of 5-hydroxytryptamine in relation to the peristaltic reflex of the rat. Brit J Pharmacol 1964, 23:14-33.
18. Grider JR, Jin J-G: Distinct populations of sensory neurons mediate the peristaltic reflex elicited by muscle stretch and mucosal stimulation. J Neurosci 1994, 14:2854-2860.
19. Grider JR: CGRP as a transmitter in the sensory pathway mediating peristaltic reflex. Am J Physiol 1994, 266:G1139-1145.
20. Grider JR, Kuemmerle JF, Jin JG: 5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1p receptors on sensory CGRP neurons. Am J Physiol 1996, 270:G778-G782.
21. Foxx-Orenstein AE, Kuemmerle JF, Grider JR: The peristaltic reflex induced by mucosal stimuli in human and guinea pig intestine is mediated by distinct mucosal 5-HT receptors. Gastroenterology 1995, 108:A600.
22. Pan H, Wade PR, Gershon MD: Activation of and transmission from intrinsic sensory neurons of the submucosal plexus. Gastroenterology 1997, 112:A803.
23. Kirchgessner AL, Tamir H, Gershon MD: 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, 12:235-249.
24. Kirchgessner AL, Liu M-T, Gershon MD: In situ identification and visualization of neurons that mediate enteric and enteropancreatic reflexes. J Comp Neurol 1996, 371:270-286.
25. Furness JB, Kunze WA, Bertrand PP, Clerc N, Bornstein JC: Intrinsic primary afferent neurons of the intestine. Prog Neurobiol 1998, 54:1-18.
26. Kunze WA, Bornstein JC, Furness JB: Identification of sensory nerve cells in a peripheral organ (the intestine) of a mammal. Neuroscience 1995, 66:1-4.
27. Furness JB, Johnson PJ, Pompolo S, Bornstein JC: Evidence that enteric motility reflexes can be initiated through entirely intrinsic mechanisms in the guinea-pig small intestine. Neurogastroenterol Mot 1995, 7:89-96.
28. Bertrand PP, Kunze WAA, Bornstein JC, Furness JB, Smith ML: Analysis of the responses of myenteric neurons in the small intestine to chemical stimulation of the mucosa. Am J Physiol 1997, 36:G422-G435.
29. Kunze WAA, Furness JB, Bertrand PP, Bornstein JC: Intracellular recording from myenteric neurons of the guinea-pig ileum that respond to stretch. J Physiol (Lond) 1998, 506:827-842.
30. Kadowaki M, Wade PR, Gershon MD: Participation of 5-HT3, 5-HT4, and nicotinic receptors in the peristaltic reflex of the guinea pig distal colon. Am J Physiol 1996, 271:G849-G857.
31. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD: Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci 1996, 16:2352-2364.
32. Chen J-X, Pan H, Rothman TP, Wade PR, Gershon MD: Guinea pig 5-HT transporter: cloning, expression, distribution and function in intestinal sensory reception. Am J Physiol 1998, 275:G433-G448. This article describes the effect of the 5-HT transporter, SERT, in the inactivation of 5-HT and demonstrates its role in mucosal serotonergic signaling. It is a critical article that for the first time makes clear how 5-HT can be a signaling molecule in a tissue that would not otherwise be able to terminate the effects of 5-HT.
33. Sidhu M, Cooke HJ: Role for 5-HT and ACh in submucosal reflexes mediating colonic secretion. Am J Physiol (Gastointest Liver Physiol) 1995, 269:G346-G351.
34. Cooke HJ, Sidhu M, Wang Y-Z: 5-HT activates neural reflexes regulating secretion in the guinea-pig colon. Neurogastroenterol Mot 1997, 9:181-186.
35. Grider JR, Foxx-Orenstein AE, Ji-Guang J: 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998, 115:370-380. This is an elegant article from a major laboratory that dissects the pharmacology of serotonergic reflex initiation. It presents the foremost and most compelling evidence for the participation of the 5-HT4 receptor subtype in reflex initiation.
36. Frieling T, Cooke HJ, Wood JD: Serotonin receptors on submucous neurons in guinea pig colon. Am J Physiol 1991, 261:G1017-G1023.
37. Jin JG, Foxx-Orenstein AE, Grider JR: Propulsion in guinea pig colon induced by 5-hydroxytruyptamine vie 5-HT4 and 5-HT3 receptors. J Pharmacol Exp Ther 1999, 288:93-97. This second article from the Grider laboratory is quite definitive and explains the uncomfortable side effects of treatment with 5-HT3 antagonists.
38. Hillsley K, Grundy D: Sensitivity to 5-hydroxytryptamine in different afferent subpopulations within mesenteric nerves supplying the rat jejunum. J Physiol (Lond) 1998, 509:717-727. This is a most important article in showing the effects of 5-HT3 receptors on extrinsic primary afferent nerves.
39. Blackshaw LA, 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, 45:41-50.
40. Grundy D, Blackshaw LA, Hillsley K: Role of 5-hydroxytryptamine in gastrointestinal chemosensitivity. Dig Dis Sci 1994, 39(12 suppl.):44S-47S.
41. Hillsley K, Kirkup AJ, Grundy D: Direct and indirect actions of 5-hydroxytryptamine on the discharge of mesenteric afferent fibers innervating the rat jejunum. J Physiol (Lond) 1998, 506:551-561. This article presents an important distinction between the direct and the indirect effects of 5-HT on afferent neural discharge.
42. Gregory RE, Ettinger DS: 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: a comparison of their pharmacology and clinical efficacy. Drugs 1998, 55:173-189.
43. Rudd JA, Naylor RJ: Effects of 5-HT3 receptor antagonists on models of acute and delayed emesis induced by cisplatin in the ferret. Neuropharmacology 1994, 33:1607-1608.
44. Nagakura Y, Kontoh A, Tokita K, Tomoi M, Shimomura K, Kadowaki M: Combined blockade of 5-HT3- and 5-HT4-serotonin receptors inhibits colonic functions in conscious rats and mice. J Pharmacol Exp Ther 1997, 281:284-290.
45. Fuller RW, Wong DT: Serotonin uptake and serotonin uptake inhibition. Ann NY Acad Sci 1990, 600:68-80.
46. Gershon MD, Robinson R, Ross LL: Serotonin accumulation in the guinea pig's myenteric plexus: ion dependence, structure activity relationship and the effect of drugs. J Pharmacol Exp Ther 1976, 198:548-561.
47. Robinson R, Gershon MD: Synthesis and uptake of 5-hydroxytryptamine by the myenteric plexus of the small intestine of the guinea pig. J Pharmacol Exp Ther 1971, 178:311-324.
48. Gershon MD, Altman RF: An analysis of the uptake of 5-hdyroxytryptamine by the myenteric plexus of the small intestine of the guinea pig. J Pharmacol Exp Ther 1971, 179:29-41.
49. Gershon MD, Jonakait GM: Uptake and release of 5-hydroxytryptamine by enteric serotonergic neurons: effects of fluoxetine (Lilly 110140) and chlorimipramine. Brit J Pharmacol 1979, 66:7-9.
50. Dreyfus CF, Sherman D, Gershon MD: Uptake of serotonin by intrinsic neurons of the myenteric plexus grown in organotypic tissue culture. Brain Res 1977, 128:109-123.
51. Chang AS, Chang SM, Starnes DM, Schroeter S, Bauman AL, Blakely RD: Cloning and expression of the mouse serotonin transporter. Mol. Brain Res 1996, 43:185-192.
52. Blakely RD, Berson HE, Fremeau RT, Caron MG, Peek MM, Prince HK, Bradley CC: Cloning and expression of a functional serotonin transporter from rat brain. Nature 1991, 354:66-70.
53. Gershon MD, Sherman DL, Pintar JE: Type-specific localization of monoamine oxidase in the enteric nervous system: relatonship to 5-hydroxytryptamine, neuropeptides, and sympathetic nerves. J Comp Neurol 1990, 301:191-213.
54. Trindade E, Menon D, Topfer LA, Coloma C: Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. Can Med Assoc J 1998, 159:1245-1252. This article nicely illustrates the downside of administration of SSRIs and other SERT inhibitors.
55. Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, et al.: Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. Mol Pharmacol 1998, 53:649-655. This important article describes the knockout of the gene encoding SERT in mice. This animal is likely to be extremely valuble in understanding the function(s) of 5-HT in the gut.
56. Gorard DA, Libby GW, Farthing MJ: 5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake. Gut 1994, 35:496-500.
57. Gershon MD, Ross LJ: Studies on the relationship of 5-hydroxytryptamine and the enterochromaffin cell to anaphylatic shock in mice. J Exp Med 1962, 115:367-382.
58. Shigematsu T, Miura S, Hirokawa M, Hokari R, Higuchi H, Tsuzuki Y, et al.: Endothelins promote egg albumin-induced intestinal anaphylaxis in rats. Gastroenterology 1998, 115:348-356.
59. Palmer JM, Wong-Riley M, Sharkey KA: Functional alterations in jejunal myenteric neurons during inflammation in nematode-infected guinea pigs. Am J Physiol 1998, 275:G922-G935.
60. Busch AE, Quester S, Ulzheimer JC, Waldegger S, Gorboulev V, Arndt P, et al.: Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1. J Biol Chem 1996, 271:32599-32604.
61. Grundemann D, Babin-Ebell J, Martel F, Ording N, Schmidt A, Schomig E: Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells. J Biol Chem 1997, 18:10408-10413.
62. Grundemann D, Koster S, Kiefer N, Breidert T, Engelhardt M, Spitzenberger F, et al.: Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J Biol Chem 1998, 273:30915-30920. This article presents an alternative to SERT for inactivating 5-HT, which may function when SERT is knocked out or chronically inhibited. In addition to promoting the survival of mice lacking SERT, the organic cation transporters may also be critical in inactivating 5-HT in individuals treated with SSRIs or taking cocaine.
63. Urakami Y, Okuda M, Mauda S, Saito H, Inui KI: Functional characteristics and membrane localizations of rat multispecific organic cantion transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp Ther 1998, 287:800-805. This article, reference 62, presents an alternative to SERT that may function when SERT is knocked out or chronically inhibited.
64. Farthing MJ: New drugs in the management of the irritable bowel syndrome. Drugs 1998, 56:11-21. This article provides good insight into the treatment of IBS.
65. Wells NE, Hahn BA, Whorwell PJ: Clinical econimis review: irritable bowel syndrome. Aliment Pharmacol Ther 1997, 11:1019-1030.
66. Talley NJ: Scope of the problem of functional digestive disorders. Eur J Surg Suppl 1998, 582:35-41.
67. Hamm LR, Sorrells SC, Harding JP, Northcutt AR, Heath AT, Kapke GF, et al.: Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome criteria. Am J Gastroenterol 1999, 94:1279-1282.
68. Drossman DA: Review article: an integrated approach to the irritable bowel syndrome. Aliment Pharmacol Ther 1999, 13(suppl. 2):3-14.
69. Kay L, Jorgensen T, Lanng C: Irritable bowel syndrome: which definitions are consistent? J Intern Med 1998, 244:489-494.
70. Talley NJ: Irritable bowel syndrome: disease definition and symptom description. Eur J Surg Suppl 1998, 583:24-28.
71. Camilleri M: What's in a name? Roll on Rome II [editorial]. Gastroenterology 1998, 114:237.
72. Drossman DA: Irritable bowel syndrome. Gastroenterologist 1994, 2:315-26.
73. Talley NJ, Boyce PM, Jones M: Is the association between irritable bowel syndrome and abuse explained by neuroticism? A population based study. Gut 1998, 42:47-53.
74. Humphrey PP, Bountra C, Clayton N, Kozlowski K: Review article: the therapeutic potential of 5-HT3 receptor antagonists in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 1999, 13 (suppl. 2):31-38.
75. Mangel AW, Northcutt AR: Review article: the safety and efficacy of alosetron, a 5-HT3 receptor antagonist, in female irritable bowel syndrome patients. Aliment Pharmacol Ther 1999, 13 (suppl. 2):77-82. Description of the successes and limitations of the first drug ever accepted by a panel of the Food and Drug Administration as safe and effective for the treatment of IBS. This is a major clinical advance. This article provides a definitive evaluation of alosetron.
76. Camilleri M, Mayer EA, Drossman DA1 Heath A, Dukes GE, McSorley D, et al.: Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther 1999, 13:1149-1159. This article presents clinical evidence that alosetron is effective against IBS.
77. Gunput MD: Review article: clinical pharmacology of alosetron. Aliment Pharmacol Ther 1999, 13 (suppl. 2):70-76.
78. Delvaux M, Louvel D, Mamet JP, Campos-Oriola R, Frexinos J: Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1998, 12:849-855.
79. Bardhan K, Bodemar G, Geldof H, Schultz E, Snell C, Darekar B: A double-blind placebo-controlled study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome (IBS). Gastroenterology 1996, 110:A630.
80. Bearcroft CP, Perrett D, Farthing MJ: Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study. Gut 1998, 42:42-46. The authors support the idea that IBS involves the abnormal secretion and/or inactivation of 5-HT in the gut.
81. Zhai J, Gershon MD, Walsh J, Wong H, Kirchgessner AL: Inward currents in neurons from newborn guinea pig intestine: mediation by 5-HT3 receptors. J Pharmacol Exp Ther 1999, 291:374-382. The authors present a noteworthy characterization of the effects of the 5-HT3 receptor on enteric neurons. It makes a good counterpoint to the even more elegant article, reference 82.
82. Zhou X, Galligan JJ: Synaptic activation and properties of 5-hydroxytryptamine3 receptors in myenteric neurons of guinea pig intestine. J Pharmacol Exp Ther 1999, 290:803-810. This is a state-of-the-art characterization of the 5-HT3 receptor of myenteric neurons and presents the first evidence that 5-HT mediates fEPSPs, as well as the previously known, slow EPSPs (via the 5-HT1P receptor) in the ENS.
83. Galligan JJ: Electrophyiological studies of 5-hydroxytryptamine receptors on enteric neurons. Behav Brain Res 1996, 73:199-201.
84. Lesch K-P, Bengel D, Heils D, Sabol SZ, Greenberg BD, Petri S, et al: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274:1527-1530.
85. Lesch K-P, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P: Organization of the human serotonin transporter gene. J Neural Transm 1994, 95:157-162.
86. Kimmel SE, Keane MG, Crary JL, Jones J, Kinman JL, Beare J, et al.: Detailed examination of fenfluramine-phentermine users with valve abnormalities identified in Fargo, North Dakota [see comments]. Am J Cardiol 1999, 84:304-308.
87. Pham TD, Gershon MD, Rothman TP: Time of origin of neurons in the murine enteric nervous system. J Comp Neurol 1991, 314:789-798.
88. Fiorica-Howells E, Maroteaux L, Gershon MD: Serotonin and the 5-HT2B receptor in the development of enteric neurons. J Neurosci 2000, 20:294-305. These authors are the first to show that 5-HT is an enteric growth factor and the first to demonstrate a physiologic role in development of the 5-HT2B receptor.