What is produced largely by neurons in the brain stem and acts both as a neurotransmitter and a hormone?

1. Rapport MM, Green AA, Page IH. Serum vasoconstrictor, serotonin; isolation and characterization. J. Biol. Chem. 1948;176:1243–51. [PubMed] [Google Scholar]

2. Roth BL, editor. The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics. Totowa, NJ: Humana; 2007. [Google Scholar]

3. Roth BL. Multiple serotonin receptors: clinical and experimental aspects. Ann. Clin. Psychiatry. 1994;6:67–78. [PubMed] [Google Scholar]

4. Roth BL, Xia Z. Molecular and cellular mechanisms for the polarized sorting of serotonin receptors: relevance for genesis and treatment of psychosis. Crit. Rev. Neurobiol. 2004;16:229–36. [PubMed] [Google Scholar]

5. Kroeze WK, Kristiansen K, Roth BL. Molecular biology of serotonin receptors: structure and function at the molecular level. Curr. Top. Med. Chem. 2002;2:507–28. [PubMed] [Google Scholar]

6. Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28:519–26. [PubMed] [Google Scholar]

7. Roth BL. Drugs and valvular heart disease. N. Engl. J. Med. 2007;356:6–9. [PubMed] [Google Scholar]

8. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414. [PubMed] [Google Scholar]

9. Mengod G, Vilaro MT, Cortes R, et al. Chemical neuroanatomy of 5-HT receptor subtypes in the mammalian brain. In: Roth BL, editor. The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics. Totowa, NJ: Humana; 2007. pp. 319–64. [Google Scholar]

10. Araneda R, Andrade R. 5-Hydroxytryptamine 2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience. 1991;40:399–412. [PubMed] [Google Scholar]

11. Airan RD, Meltzer LA, Roy M, et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science. 2007;317:819–23. [PubMed] [Google Scholar]

12. Canli T, Lesch KP. Long story short: the serotonin transporter in emotion regulation and social cognition. Nat. Neurosci. 2007;10:1103–9. [PubMed] [Google Scholar]

13. Roth BL, Hanizavareh SM, Blum AE. Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl.) 2004;174:17–24. [PubMed] [Google Scholar]

14. Gross C, Hen R. The developmental origins of anxiety. Nat. Rev. Neurosci. 2004;5:545–52. [PubMed] [Google Scholar]

15. Lesch KP. Serotonergic gene inactivation in mice: models for anxiety and aggression? Novartis Found. Symp. 2005;268:111–40. [PubMed] [Google Scholar]

16. Giorgetti M, Tecott LH. Contributions of 5-HT2C receptors to multiple actions of central serotonin systems. Eur. J. Pharmacol. 2004;488:1–9. [PubMed] [Google Scholar]

17. Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol. Psychiatry. 2007;12:904–22. [PubMed] [Google Scholar]

18. Schechter LE, Ring RH, Beyer CE, et al. Innovative approaches for the development of antidepressant drugs: current and future strategies. NeuroRx. 2005;2:590–611. [PMC free article] [PubMed] [Google Scholar]

19. Kaumann AJ, Levy FO. 5-hydroxytryptamine receptors in the human cardiovascular system. Pharmacol. Ther. 2006;111:674–706. [PubMed] [Google Scholar]

20. Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27:1293–300. [PubMed] [Google Scholar]

21. Ni W, Watts SW. 5-hydroxytryptamine in the cardiovascular system: focus on the serotonin transporter (SERT) Clin. Exp. Pharmacol. Physiol. 2006;33:575–83. [PubMed] [Google Scholar]

22. Carneiro AM, Cook EH, Murphy DL, Blakely RD. Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J. Clin. Invest. 2008;118:1544–52. [PMC free article] [PubMed] [Google Scholar]

23. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation. 2003;108:32–36. [PubMed] [Google Scholar]

24. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch. Gen. Psychiatry. 2005;62:792–98. [PubMed] [Google Scholar]

25. Glassman AH. Does treating postmyocardial infarction depression reduce medical mortality? Arch. Gen. Psychiatry. 2005;62:711–12. [PubMed] [Google Scholar]

26. Somberg TC, Arora RR. Depression and heart disease: therapeutic implications. Cardiology. 2008;111:75–81. [PubMed] [Google Scholar]

27. Walther DJ, Peter JU, Winter S, et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell. 2003;115:851–62. [PubMed] [Google Scholar]

28. Dale GL. Coated-platelets: an emerging component of the procoagulant response. J. Thromb. Haemost. 2005;3:2185–92. [PubMed] [Google Scholar]

29. Langer C, Piper C, Vogt J, et al. Atrial fibrillation in carcinoid heart disease: the role of serotonin. A review of the literature. Clin. Res. Cardiol. 2007;96:114–18. [PubMed] [Google Scholar]

30. Singh S. Trials of new antiarrhythmic drugs for maintenance of sinus rhythm in patients with atrial fibrillation. J. Interv. Cardiol. Electrophysiol. 2004;10(Suppl. 1):71–76. [PubMed] [Google Scholar]

31. Brattelid T, Qvigstad E, Lynham JA, et al. Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4mRNAin heart failure. Naunyn Schmiedebergs Arch. Pharmacol. 2004;370:157–66. [PubMed] [Google Scholar]

32. Birkeland JA, Sjaastad I, Brattelid T, et al. Effects of treatment with a 5-HT4 receptor antagonist in heart failure. Br. J. Pharmacol. 2007;150:143–52. [PMC free article] [PubMed] [Google Scholar]

33. Doggrell SA. The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation. Expert Opin. Investig. Drugs. 2003;12:805–23. [PubMed] [Google Scholar]

34. Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836–41. [PubMed] [Google Scholar]

35. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol. Pharmacol. 2003;63:1223–29. [PubMed] [Google Scholar]

36. Nebigil CG, Maroteaux L. Functional consequence of serotonin/5-HT2B receptor signaling in heart: role of mitochondria in transition between hypertrophy and heart failure? Circulation. 2003;108:902–8. [PubMed] [Google Scholar]

37. Kereveur A, Callebert J, Humbert M, et al. High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler. Thromb. Vasc. Biol. 2000;20:2233–39. [PubMed] [Google Scholar]

38. Esteve JM, Launay JM, Kellermann O, Maroteaux L. Functions of serotonin in hypoxic pulmonary vascular remodeling. Cell. Biochem. Biophys. 2007;47:33–44. [PubMed] [Google Scholar]

39. Launay JM, Herve P, Peoc’h K, et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 2002;8:1129–35. [PubMed] [Google Scholar]

40. Deraet M, Manivet P, Janoshazi A, et al. The natural mutation encoding a C terminus–truncated 5-hydroxytryptamine 2B receptor is a gain of proliferative functions. Mol. Pharmacol. 2005;67:983–91. [PubMed] [Google Scholar]

41. Guilluy C, Rolli-Derkinderen M, Tharaux PL, et al. Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J. Biol. Chem. 2007;282:2918–28. [PubMed] [Google Scholar]

42. Marcos E, Adnot S, Pham MH, et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2003;168:487–93. [PubMed] [Google Scholar]

43. Eilers H, Schumacher MA. Opioid-induced respiratory depression: Are 5-HT4a receptor agonists the cure? Mol. Interv. 2004;4:197–99. [PubMed] [Google Scholar]

44. Manzke T, Guenther U, Ponimaskin EG, et al. 5-HT4a receptors avert opioid-induced breathing depression without loss of analgesia. Science. 2003;301:226–29. [PubMed] [Google Scholar]

45. Kinney HC, Filiano JJ, White WF. Medullary serotonergic network deficiency in the sudden infant death syndrome: review of a 15-year study of a single dataset. J. Neuropathol. Exp. Neurol. 2001;60:228–47. [PubMed] [Google Scholar]

46. Paterson DS, Trachtenberg FL, Thompson EG, et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA. 2006;296:2124–32. [PubMed] [Google Scholar]

47. Richerson GB, Wang W, Tiwari J, Bradley SR. Chemosensitivity of serotonergic neurons in the rostral ventral medulla. Respir. Physiol. 2001;129:175–89. [PubMed] [Google Scholar]

48. Erickson JT, Shafer G, Rossetti MD, et al. Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges. Respir. Physiol. Neurobiol. 2007;159:85–101. [PMC free article] [PubMed] [Google Scholar]

49. Tecott LH, Abdallah L. Mouse genetic approaches to feeding regulation: serotonin 5-HT2C receptor mutant mice. CNS Spectr. 2003;8:584–88. [PubMed] [Google Scholar]

50. Lam DD, Heisler LK. Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes. Expert Rev. Mol. Med. 2007;9:1–24. [PubMed] [Google Scholar]

51. Lam DD, Przydzial MJ, Ridley SH, et al. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology. 2008;149:1323–28. [PMC free article] [PubMed] [Google Scholar]

52. Hodges MR, Tattersall GJ, Harris MB, et al. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. J. Neurosci. 2008;28:2495–505. [PMC free article] [PubMed] [Google Scholar]

53. Hedlund PB, Kelly L, Mazur C, et al. 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents. Eur. J. Pharmacol. 2004;487:125–32. [PubMed] [Google Scholar]

54. Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress. Eur. J. Pharmacol. 2003;463:235–72. [PubMed] [Google Scholar]

55. Matsuda M, Imaoka T, Vomachka AJ, et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell. 2004;6:193–203. [PubMed] [Google Scholar]

56. Stull MA, Pai V, Vomachka AJ, et al. Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. Proc. Natl. Acad. Sci. USA. 2007;104:16708–13. [PMC free article] [PubMed] [Google Scholar]

57. Lesurtel M, Graf R, Aleil B, et al. Platelet-derived serotonin mediates liver regeneration. Science. 2006;312:104–7. [PubMed] [Google Scholar]

58. Tecott LH. Serotonin and the orchestration of energy balance. Cell. Metab. 2007;6:352–61. [PubMed] [Google Scholar]

59. Roper SD. Cell communication in taste buds. Cell. Mol. Life Sci. 2006;63:1494–500. [PMC free article] [PubMed] [Google Scholar]

60. Suzuki A, Naruse S, Kitagawa M, et al. 5-hydroxytryptamine strongly inhibits fluid secretion in guinea pig pancreatic duct cells. J. Clin. Invest. 2001;108:749–56. [PMC free article] [PubMed] [Google Scholar]

61. Minami M, Endo T, Hirafuji M, et al. Pharmacological aspects of anticancer drug–induced emesis with emphasis on serotonin release and vagal nerve activity. Pharmacol. Ther. 2003;99:149–65. [PubMed] [Google Scholar]

62. Sommer C. Serotonin in pain and analgesia: actions in the periphery. Mol. Neurobiol. 2004;30:117–25. [PubMed] [Google Scholar]

63. Braz JM, Basbaum AI. Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits. J. Comp. Neurol. 2008;507:1990–2003. [PMC free article] [PubMed] [Google Scholar]

64. Jann MW, Slade JH. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy. 2007;27:1571–87. [PubMed] [Google Scholar]

65. Mukaida K, Shichino T, Koyanagi S, et al. Activity of the serotonergic system during isoflurane anesthesia. Anesth. Analg. 2007;104:836–39. [PubMed] [Google Scholar]

66. Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med. J. Aust. 2007;187:361–65. [PubMed] [Google Scholar]

67. de Jong TR, Veening JG, Waldinger MD, et al. Serotonin and the neurobiology of the ejaculatory threshold. Neurosci. Biobehav. Rev. 2006;30:893–907. [PubMed] [Google Scholar]

68. Giuliano F. 5-Hydroxytryptamine in premature ejaculation: opportunities for therapeutic intervention. Trends Neurosci. 2007;30:79–84. [PubMed] [Google Scholar]

69. Ramage AG. The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control of micturition. Br. J. Pharmacol. 2006;147(Suppl. 2):S120–31. [PMC free article] [PubMed] [Google Scholar]

70. Basu M, Duckett J. The treatment of urinary incontinence with duloxetine. J. Obstet. Gynaecol. 2008;28:166–69. [PubMed] [Google Scholar]

71. Bolte AC, van Geijn HP, Dekker GA. Pathophysiology of preeclampsia and the role of serotonin. Eur. J. Obstet. Gynecol. Reprod. Biol. 2001;95:12–21. [PubMed] [Google Scholar]

72. Gupta S, Hanff LM, Visser W, et al. Functional reactivity of 5-HT receptors in human umbilical cord and maternal subcutaneous fat arteries after normotensive or pre-eclamptic pregnancy. J. Hypertens. 2006;24:1345–53. [PubMed] [Google Scholar]

73. Dawes SD. Can SSRIs reduce the risk of preeclampsia in pregnant, depressed patients? Med. Hypotheses. 2005;64:33–36. [PubMed] [Google Scholar]

74. Salkeld E, Ferris LE, Juurlink DN. The risk of postpartum hemorrhage with selective serotonin reuptake inhibitors and other antidepressants. J. Clin. Psychopharmacol. 2008;28:230–34. [PubMed] [Google Scholar]

75. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N. Engl. J. Med. 2006;354:579–87. [PubMed] [Google Scholar]

76. Minosyan TY, Lu R, Eghbali M, et al. Increased 5-HT contractile response in late pregnant rat myometrium is associated with a higher density of 5-HT2A receptors. J. Physiol. 2007;581:91–97. [PMC free article] [PubMed] [Google Scholar]

77. Oropeza MV, Ponce Monter H, Reynoso Isla M, Campos MG. The ovarian and cervical regions of the rat uterus display a different contractile response to serotonin and prostaglandin F2αI. The estrous cycle. Life Sci. 2000;66:PL345–51. [PubMed] [Google Scholar]

78. Jeffrey JJ, Ehlich LS, Roswit WT. Serotonin: an inducer of collagenase in myometrial smooth muscle cells. J. Cell Physiol. 1991;146:399–406. [PubMed] [Google Scholar]

79. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol. Psychiatry. 2007;12:331–59. [PubMed] [Google Scholar]

80. Weintraub M, Hasday JD, Mushlin AI, Lockwood DH. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med. 1984;144:1143–48. [PubMed] [Google Scholar]

81. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluraminephentermine. N. Engl. J. Med. 1997;337:581–88. [PubMed] [Google Scholar]

82. Fitzgerald LW, Burn TC, Brown BS, et al. Possible role of valvular serotonin 5-HT2B receptors in the cardiopathy associated with fenfluramine. Mol. Pharmacol. 2000;57:75–81. [PubMed] [Google Scholar]

83. O’Connor KA, Roth BL. Finding new tricks for old drugs: an efficient route for public-sector drug discovery. Nat. Rev. Drug Discov. 2005;4:1005–14. [PubMed] [Google Scholar]

84. Droogmans S, Cosyns B, D’Haenen H, et al. Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease. Am. J. Cardiol. 2007;100:1442–45. [PubMed] [Google Scholar]

85. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N. Engl. J. Med. 2007;356:29–38. [PubMed] [Google Scholar]

86. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N. Engl. J. Med. 2007;356:39–46. [PubMed] [Google Scholar]

Page 2

Central serotonergic pathways, effects, and drugs. In the central nervous system (CNS), serotonin is almost exclusively produced in neurons originating in the raphe nuclei located in the midline of the brainstem. These serotonin-producing neurons form the largest and most complex efferent system in the human brain. The most caudal raphe innervate the spinal cord, while the more rostral raphe, the dorsal raphe nucleus and the medial raphe nucleus, innervate much of the rest of the CNS by diffuse projections. Indeed, virtually every cell in the brain is close to a serotonergic fiber, and nearly all behaviors as well as many other brain functions are regulated by serotonin. Not surprisingly, serotonin receptors and transporters are a major focus of CNS drug development, and many current medications modulate serotonin neurotransmission. 5-HT, serotonin; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor.