Anatomy. Cell Biology and Maturation of the Serotonergic System:

Neurotrophic Implications for the Actions of Psychotrophic Drugs

Efrain C. Azmitia, Ph.D.
Department of Biology
New York University
Washington Square East
New York, New York, 10003
Phone: 212-998-8235
Fax: 212-995-4175

Patricia M. Whitaker-Amitia, Ph.D.
Department of Psychology
State University of New York
Stony Brook, New York 11791
Phone: 212-998-8235
Fax: 212-995-4175


1. Akbari HM, Whitaker-Azmitia PM, Azmitia EC. In utero exposure to cocaine results in a decreased of the tropic factor S-100b and microcephaly: reversal by postnatal 5-HT1A agonist treatment. Neurosci Lett 1994 170:141-144.

2. Altman J, Bayer SA. Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. J Comp Neurol 1990;301:325-342.

3. Anorexia nervosa: directions for future research. Study Group on Anorexia Nervosa. Int J Eat Disord 1995;17:235-241.

4. Arango V, Underwood M, Gubbi A, Mann J. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 1995;688:121-133.

5. Azmitia EC. The serotonin producing neurons of the midbrain median and dorsal raphe nuclei. In: LL Iversen, SD Iversen, Snyder S, eds. The handbook of psychopharmacology, vol. 9. New York: Plenum Press, 1978:233-314.

6. Azmitia EC. Bilateral serotonergic projections to the dorsal hippocampus of the rat: simultaneous localization of 3H-5HT and HRP after retrograde transport. J Comp Neurol 1981;203:737-743.

7. Azmitia EC. The primate serotonergic system: progression towards a collaborative organization. In: Meltzer H, ed. Psychopharmacology: A third generation of progress. New York: Plenum, 1987;61-74.

8. Azmitia EC. Brain Chemicals. In: Ramachandran VS, ed. Encyclopedia of human behavior. San Diego, New York, Boston, London, Sydney, Tokyo, Toronto.:Academic Press Inc., 1994;435-441.

9. Azmitia EC, Algeri S, Costa E. In vivo conversion of 3H-L-tryptophan into 3H-L-serotonin in brain areas of adrenalectomized rats. Science 1970;169:201-203.

10. Azmitia EC, Brennan MJ, Quartermain D. Adult development of the hippocampal-serotonin system of C57BL/6N mice; analysis of high-affinity uptake of 3H-5HT in slices and synaptosomes. Int J Neurochem 1983;5:39-44.

11. Azmitia EC, Buchan AM, Williams JH. Structural and functional restoration by collateral sprouting of hippocampal 5-HT axons. Nature 1978;274:374-377

12. Azmitia EC, Davila M, Frankfurt M, Whitaker-Azmitia PM, Zhou FC. Plasticity of fetal and adult CNS serotonergic neurons: role of growth-regulatory factors. Ann NY Acad Sci 1990;16:343-365.

13. Azmitia EC, Dolan K, Whitaker-Azmitia PM. S-100b but not NGF, EGF, insulin or calmodulin functions as a CNS serotonergic growth factor. Brain Res 1990;516:354-356.

14. Azmitia EC, Gannon PJ. Anatomy of the serotonergic system in the primate and sub-primate brain. Adv Neurol 1986;43:407-468.

15. Azmitia EC, Griffin WST, Marshak DR, Van Eldik LJ, Whitaker-Azmitia PM. S100b and serotonin: a possible astrocytic-neuronal link to neuropathology of Alzheimer's disease. Prog Brain Res 1992;94:459-473.

16. Azmitia EC, Liao B, Chen Y. Effects of dexamethasone on tryptophan hydroxylase protein in adrenalectomized rats: immunocytochemical and western analysis using a specific antipeptide antibody. J Neurosci 1993;13:5041-5055.

17. Azmitia EC, Liao B. Dexamethasone reverses adrenalectomy-induced de-differentiation in midbrain raphe-axis. Ann NY Acad Sci 1994;746:180-193.

18. Azmitia EC, McEwen BS. Corticosterone regulation of tryptophan hydroxylase in midbrain of the rat. Science 1969;166:1274-1276.

19. Azmitia EC, Rubinstein VJ, Strafaci JA, Rios JC, Whitaker-Azmitia PM. 5-HT1A agonist and dexamethasone reversal of para-chloroamphetamine induced loss of MAP-2 and synaptophysin immunoreactivity in adult rat brain. Mol Brain Res 1995;677:181-192.

20. Azmitia EC, Segal M. An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 1978;179:641-659.

21. Azmitia EC, Whitaker-Azmitia PM. Awakening the sleeping giant: Anatomy and plasticity of the brain serotonergic system. J Clin Psychiatry 1991;52:4-16.

22. Azmitia EC, Whitaker-Azmitia PM, Bartus R. Use of tissue culture model to study neuronal regulatory trophic and toxic factors in the aged brain. Neurobiol Aging 1988;9:743-758.

23. Azmitia EC, Whitaker-Azmitia PM, Kheck N, Gannon P. The cellular localization of the 5-HT1A receptor in primate cortex, hippocampus and brainstem neurons and glial cells. Neuropsychopharmacology 1996;14:35-46.

24. Azmitia EC, Yu I, Akbari HM, Kheck N, Whitaker-Azmitia PM, Marshak DR. Antipeptide antibodies against the 5-HT1A receptor. J Chem Neuroanat 1992;5:289-298.

25. Baker KG, Halliday GM, Törk I. Cytoarchitecture of the human dorsal raphe nucleus. J Comp Neurol 1990;301:147-161.

26. Bar-Peled O, Gross-Isseroff R, Ben-Hur H, Hoskins I, Groner Y, Biegon A. Fetal brain exhibits a prenatal peak in the number of 5-HT1A receptors. Neurosci Lett 1991;127:173-176.

27. Bazelon M, Paine RS, Coeiw VA, Hunt P, Houck JC, Mahanand D. Reversal of hypotonia in infants with Down's syndrome by administration of 5-hydroxytryptophan. Lancet 1967;1:1130-1133.

28. Becker LE, Mito T, Takashima S, Onodera K, Friend WC. Association of phenotypic abnormalities of Down's syndrome with an imbalance of genes on chromosome 21. APMIS 1993;=+Suppl 40:57-70.

29. Berger UV, Gu XF, Azmitia EC. The substituted amphetamines methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-HT release via a common mechanism which is blocked by fluoxetine and cocaine. Eur J Pharmacol 1992;215:153-160.

30. Blue ME, Erzurumlu RS, Jhaveri S. A comparison of pattern formation by thalamocortical and serotonergic afferent in the rat barrel field cortex. Cereb Cortex 1991;1:380-389.

31. Boadle-Biber MC, Corley KC, Graves L, Phan T, Rosecrans J. Increase in the activity of tryptophan hydroxylase from cortex and midbrain of male Fischer 344 rats in response to acute or repeated sound stress. Brain Res 1989;482:306-316.

32. Bogdanski DF, Brodie BB. Role of sodium and potassium ions in storage of norepinephrine by sympathetic nerve endings. Life Sci 1966;5:1563.

33. Bohn MC, Lauder JM. Cerebellar granule cell genesis in the hydrocortisone-treated rat. Dev Neurosci 1980;3:81-89.

34. Bowen DM, White P, Spillane JA, et al. Accelerated aging or selective neuronal loss as an important cause of dementia? Lancet 1979;1:11-14

35. Brady KT, Sonne SC, Roberts JM. Sertraline treatment of comorbid posttraumatic stress disorder and alcohol dependency. J Clin Psychiatry 1995;56:502-505.

36. Bremner JD, Randall P, Scott TM, et al. MRI based measurement of hippocampal volume in patients with combat-related posttraumatic-stress disorder. Am J Psychiatry 1995;152:973-981.

37. Brodie BB, Shore PA. On a role for serotonin and norepinephrine as chemical mediators in the central autonomic nervous system. In: Hoagland H, ed. Hormones, brain, function and behavior. New York: Academic Press, 1957.

38. Chadi G, Tinner B, Agnati LF, Fuxe K. Basic fibroblast growth factor (bFGF, FGF-2) immunoreactivity exists in the noradrenaline, adrenaline and 5-HT nerve cells of the rat brain, Neurosci Lett 1993;160:171-176.

39. Chalmers DT, Kwak SP, Mansour A, Akil H, Watson SJ. Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression. J Neurosci 1993;13:914-923.

40. Cheng L, Hamaguchi K, Ogawa M, Hamada S, Okado N. PCPA reduces both monoaminergic afferents and nonmonoaminergic synapses in the cerebral cortex. Neurosci Res 1994;19:111-115.

41. Chubakov AR, Tsyganova VG, Sarkisova EF. The stimulating influence of the raphe nuclei on the morphofunctional development of the hippocampus during their combined cultivation. Neurosci Behav Physiol 1993;23:271-276.

42. Commins DL, Axt KJ, Vosmer G, Seiden LS. Endogenously produced 5,6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine. Brain Res 1987;419:253-261.

43. Cropper EC, Eisenman JS, Azmitia EC. 5-HT-immunoreactive fibers in the trigeminal nuclear complex of the rat. Exp Brain Res 1984;55:515-522.

44. Cross AJ. Serotonin in Alzheimer's-type dementia. Ann NY Acad Sci 1990;600:405-415.

45. Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I: Demonstrations of monoamines in the cell bodies of brainstem neurons. Acta Physiol Scand 1964;62(suppl 232):1-55.

46. Davila-Garcia MI, Azmitia EC. Neuropeptides as positive or negative neuronal growth regulatory factors: effects of ACTH and leu-enkephalin on cultured serotonergic neurons. In: Lauder JM, Privat A, Giacobini E, Timiras P, Vernidakis A, eds. Molecular aspects of development and aging of the nervous system. New York: Plenum Press, 1990.

47. DeKloet ER, Kovacs GL, Szabo G, Telegdy G, Bohus B, Versteeg DHG. Decreased serotonin turnover in the dorsal hippocampus of rat brain shortly after adrenalectomy: selective normalization after corticosterone substitution. Brain Res 1982;239:659-663.

48. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotonin function and the mechanism of antidepressant action. Arch Gen Psychiatry 1990;47:411-418.

49. Eaton MJ, Staley JK, Globus MY, Whittemore SR. Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization. Dev Biol 1995;170:169-182.

50. Fisher JF, Chou AK. Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J Pharmacol Exp Ther 1979;208:203-209.

51. Gedye A. 1990 Dietary increase in serotonin reduces self-injurious behaviour in a Down's syndrome adult. J Mental Defic Res 34:195-203

52. Godridge H, Reynolds GP, Czudek C, Calcutt NA, Benton M. Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue. J Neurol Neurosurg Psychiatry 1987;50:775-778.

53. Gu XF, Azmitia EC. MDMA and PCA increases 5-HT levels extracellularly in cultured raphe cells grown in serum free media: potentiation by deprenyl and depolarization and attenuation by reserpine and nimodipine. Eur J Pharmacol 1993;235:51-57.

54. Hamon M, Bourgoin S, Henry F, Simmonet G. Activation of tryptophan hydroxylase by adenosine triphosphate, magnesium and calcium. Mol Pharmacol 1987;14:99-110.

55. Haring JH, Hagan A, Olson J, Rodgers B. Hippocampal serotonin levels influence the expression of S100B detected by immunocytochemistry. Brain Res 1993;631:119-123.

56. Haring, JH Yan, W. Effects of neonatal serotonin depletion on the development of rat dentate granule cells. Soc Neurosci Abstr 1993;19:673.

57. Haring JH, Yan W, Wilson CC. 5-HT1A Receptors mediate the effects of 5-HT on developing dentate granule cells. Soc Neurosci Abstr 1995;21:862.

58. Hentschel F, Schmidbauer M, Detzner U, Blanz B, Schmidt MH. Reversible changes in brain volume in anorexia nervosa. Z Kinder Jugenpsychiatr 1995;23:104-112.

59. Hilakivi-Clarke LA, Corduban TD, Taira T, et al. Alterations in brain monoamines and GABA A receptors in transgenic mice overexpressing TGF alpha. Pharmacol Biochem Behav 1995;50:593-600.

60. Hole K. Behavior and brain growth in rats treated with p-chlorophenylalanine in the first weeks of life. Dev Psychobiol 1972;5:157-173.

61. Huang J. Strafaci JA and Azmitia EC 5-HT1A receptor agonist reduced the adrenalectomy induced loss of the adult phenotype of granule neurons in the rat dentate gyrus. Neurochemical Res. 22, 1329-1337, 1997.

62. Imai H, Steindler DA, Kitai ST. The organization of divergent axonal projections from the midbrain raphe nuclei in the rat. J Comp Neurol 1986;243:363-380.

63. Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev 1992;72:165-229.

64. Jernigan TL, Butters N, DiTraglia G, et al. Reduced cerebral grey matter observed in alcoholics using magnetic resonance imaging. Alcohol Clin Exp Res 1991;15:418-427.

65. Joéls M, Hesen W, deKloet ER. Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA1 neurons. J Neurosci 1991;11:2288-2294.

66. Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE. Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 1993;8:315.

67. Kheck N, Gannon PJ, Azmitia EC. 5-HT1A receptor localization on the axon hillock of spinal motoneurons in primates. J Comp Neurol 1995;355:211-220.

68. Lauder, J.M. Ontogeny if neurotransmitter systems: substrates for developmental abnormalities? Mental Retard Devel Disab Res Rev 1995;1:151-168.

69. Lauder JM, Krebs H. Serotonin as a differentiation signal in early neurogenesis. Dev Neurosci 1978;1:15-30.

70. Leslie MJ, Bennett-Clarke CA, Rhoades RW. Serotonin 1B receptors form a transient vibrissa-related pattern in the primary somatosensory cortex of the developing rat. Brain Res 1992;69:143-148.

71. Levitt P, Pintar JE, Breakefield XO. Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc Natl Acad Sci USA 1982;79:6385-6389.

72. Liao B, Miesak BH, Azmitia EC. Loss of 5-HT1A receptor mRNA in the dentate gyrus of the longterm adrenalectomized rat and rapid reversal by dexamethasone. Mol Brain Res 1993;19:328-332.

73. Lidov HGW, Molliver ME. An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields. Brain Res Bull 1982;8:389-430.

74. Lindholm D, Harikka J, da Penha Berzaghi M, et al. Fibroblast growth factor-5 promotes differentiation of cultured rat septal cholinergic and raphe serotonergic neurons: comparison with the effects of neurotrophins. Eur J Neurosci 1994;6:244-252.

75. Liu JP, Lauder JM. S-100 beta and insulin-like growth factor-II differentially regulate growth of developing serotonin and dopamine neurons in vitro. J Neurosci Res 1992;33:248-256.

76. Mamounas LA, Blue ME, Siuciak JA, Altar CA. Brain-derived neuronotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 1995;15:7929-7939.

77. Meijer OC, deKloet ER. Corticosterone suppresses the expression of 5-HT1A receptor mRNA in rat dentate gyrus. Eur J Pharmacol 1994;266:255-261.

78. Mendelson SD, McEwen BS. Adrenalectomy increases the density of 5-HT1A receptors in rat hippocampus. Neuroendocrinol Lett 1990;12:353.

79. Merlio J-P, Ernfors P, Jaber M, Persson H. Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system. Neuroscience 1992;51:513-532.

80. Middlemiss DN, Palmer AM, Edel N, et al. Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin in normal and Alzheimer brain. J Neurochem 1986;9:743-758.

81. Moiseiwitsch JR, Lauder JM. Serotonin regulates mouse cranial neural crest migration. Proc Natl Acad Sci USA 1995;93:7182-7186.

82. Mower GD. Comparison of serotonin 5-HT1 receptors and innervation in the visual cortex of normal and dark-reared cats. J Comp Neurol 1991;312:223-230.

83. Niitsu Y, Hamada S, Hamaguchi K, Mikuni M, Okado N. Regulation of synaptic density by 5-HT2A receptor agonist and antagonist in the spinal cord of chicken embryo. Neurosci Lett 1995;195:159-162.

84. Nishi M, Azmitia EC. 5-HT1A receptor expression is modulated by corticosteroid receptor agonist in primary rat hippocampal culture. Brain Res 1996;722:190-194.

85. Nishi M, Poblete JC, Whitaker-Azmitia PM, Azmitia EC. Brain derived neurotrophic factor and S100b; trophic interactions on cultured serotonergic neurons. Neurosci Net 1996;10003 (

86. Nishi M, Whitaker-Azmitia PM, Azmitia EC. Effects of 5-HT-1A, S100b and steroids on synaptophysin immunoreactivity in cultured hippocampal neurons. Synapse 1996;23:1-9.

87. Olszewski J, Baxter D. Cytoarchitecture of the human brainstem. Philadelphia: JB Lippincott, 1954.

88. Page IH. The vascular action of natural serotonin, 5- and 7-hydroxytyramine and tryptamine. J Pharmacol Exper Ther 1952;105:58.

89. Poblete JC, Azmitia EC . Activation of glycogen phosphorylase by serotonin and 3,4-methylenemethamphetamine in astroglial-rich primary cultures: involvement of the 5-HT2A receptor. Brain Res 1995;680:9-15.

90. Ramón y Cajal S. Histologie du systeme nerveux de l'homme et des vertebres. France: A. Malone, 1911.

91. Ramón y Cajal. The degeneration and regeneration of the nervous system. Translated and edited by RM May. New York: Hafner, 1928.

92. Rhoades RW, Bennett-Clarke CA, Shi MY, Mooney RD. Effects of 5-HT on thalamocortical synaptic transmission in the developing rat. J Neurophysiol 1994;72:2438-2450.

93. Riad M, Emerit MB, Hamon MT. Neurotrophic effects of ipsapirone and other 5-HT1A receptor agonists on septal cholinergic neurons in culture. Dev Brain Res 1994;82:245-258.

94. Saruhashi Y, Young W. Effect of mianserin on locomotory function after thoracic spinal cord hemisection in rats. Exp Neurol 1994;29:207-216.

95. Shear PK, Jernigan TL, Butters N. Volumetric magnetic resonance imaging quantification of longitudinal brain changes in abstinent alcoholics. Alcohol Clin Exp Res 1994;18:172-176.

96. Slotkin AT. Reserpine. In: Simpson LL, Curtin DR, eds. Neuropoisons: Their pathophysiological action. New York: Plenum Press, 1974;1-69.

97. Sloviter RS, Valiquette G, Abrams GM, et al. Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 1989;243;:535-538.

98. Steinbusch HWM, Mulder AH. Immunoreactivity in the central nervous system of the rat cell bodies and terminals. Neuroscience 1981;4:557-618.

99. Sze PY. Glucocorticoids as a regulatory factor for brain tryptophan hydroxylase during development. Dev Neurosci 1980;3:217-223.

100. Tajuddin NF, Druse MJ. Treatment of pregnant alcohol consuming rats with buspirone: effects on serotonin and 5-hydroxyindoleacetic acid content in offspring. Alcohol Clin Exper Res 1993;17:110-114.

101. Tórk I. Anatomy of the serotonergic system. Ann NY Acad Sci 1990;600:9-35.

102. Tracqui P, Morot-Gaudry Y, Staub JF, et al. Model of brain serotonin metabolism. I. Structural determinants-parameter estimation. II Physiological interpretation. Am J Physiol 1983;244:R193-R206.

103. Tu JB, Zellweger H. Blood-serotonin deficiency in Down's syndrome. Lancet 1965;2:715-716.

104. Ueda S, Matsumoto Y, Nisimura A, Azmitia EC, Kawata M. Role of neuropeptide Y projection on the development of the serotonergic innervation of the suprachiasmatic nucleus of the rat, shown by triple intraocular grafts. Brain Res 1995;673:325-330.

105. Wallace JA, Lauder JM. Development of the serotonergic system in the rat embryo: an immunocytochemical study. Brain Res Bull 1983;10:459-479.

106. Waterhouse BD, Mihailoff GA, Baack JC, Woodward DJ. Topographical distribution of dorsal and median raphe neurons projecting to motor, sensorimotor and visual cortical areas in the rat. J Comp Neurol 1986;249:460-476.

107. Whitaker-Azmitia PM. Role of serotonin and other neurotransmitter receptors in brain development: Basis for developmental pharmacology. Pharmacol Rev 1991;43:553-561.

108. Whitaker-Azmitia PM, Azmitia EC. 5-Hydroxytryptamine binding to brain astroglial cells: differences between intact and homogenized preparations and mature and immature cultures. J Neurochem 1986;46:1186-1189.

109. Whitaker-Azmitia PM, Borella A, Raio N. Serotonin depletion in the adult rat causes loss of the dendritic marker MAP-2: A new animal model of schizophrenia? Neuropsychopharmacology 1995;12:269-272.

110. Whitaker-Azmitia PM, Clarke C, Azmitia EC. 5-HT1A immunoreactivity in brain astrocytes colocalized with GFAP. Synapse 1993;14:201-205.

111. Whitaker-Azmitia PM, Lauder JM, Shemer A, et al. Postnatal changes in 5-HT1 receptors following prenatal alterations in serotonin levels: further evidence for functional fetal 5-HT1 receptors. Dev Brain Res 1987;33:285-295.

112. Whitaker-Azmitia PM, Murphy R, Azmitia EC. Stimulation of astroglial 5-HT1A receptors releases the serotonin growth factor, protein S-100, and alters glial morphology. Brain Res 1990;528:155-158.

113. Woolley DW. The biochemical basis of psychosis. The serotonin hypothesis about mental diseases. New York: J. Wiley & Sons Inc., 1962.

114. Yan W, Wilson CC, Panneton WM, Haring JH. Neonatal 5-HT depletion reduces dentate granule cell spine density. Soc Neurosci Abstr 1995;21:862.

115. Zhou FC, Azmitia EC. Effect of adrenalectomy and corticosterone on the sprouting of serotonergic fibers in hippocampus. Neurosci Lett 1985;54:111-116.

116. Zhou FC, Azmitia EC. Laminin facilitates and guides fiber growth of transplanted neurons in adult brain. J Chem Neuroanat 1988;1:133-146.

117. Zhou FC, Bledsoe S, Lumeng Li T-K. Immunostained serotonergic fibers are decreased in selected brain regions of alcohol-preferring rats. Alcohol 1991;8:425-431.

published 2000