Neurotoxins That Affect Central Serotoninergic Systems

  • Tomás A. Reader
  • Karen M. Dewar


The last 30 years have witnessed an explosive increase in our knowledge of neuronal communication in the central nervous system (CNS), mainly due to the methodological progress which has made it possible to identify neurons and neuronal networks by the chemical substance they use as their transmitter. Historically, the first chemically-identified neurotransmitter systems were found to utilize aromatic monoamines; either the catecholamines noradrenaline (NA), adrenaline (AD) and dopamine (DA) or the indoleamine serotonin (5-hydroxytryptamine, 5-HT). The first comprehensive descriptions of central 5-HT were based on biochemical determinations of this aromatic monoamine in different brain regions 1–4 and very soon followed by the use of histofluorescent microscopy 5–9, measurements of tryptophan hydroxylase 10, immunocytochemical surveys using antibodies against 5-HT itself 11 as well as autoradiographic tracing procedures based on uptake properties of the 5-HT system. 12–15 A strategy in the study of a particular nerve function that has been widely accepted has been to remove surgically either a nerve or the ganglion from which the nerve originates, and then establish the characteristics, magnitude and extent of the functional loss. In the particular case of aromatic monoamine neurotransmitters, this approach can be exemplified by the work pioneered by Cannon 16 in the sympathetic nervous system, and by the use of immunosympathectomies using antibodies againts nerve growth factor 17. The research on central catecholamine and 5-HT systems has benefited from the use of different drugs and agents used as chemical scalpels to dissect out the different projections and at the same time this strategy provided interesting models for the study of changes in sensitivity, uptake mechanisms, behavioural modifications, axonal sprouting and plasticity. The first compound used as a selective neurotoxin for the catecholamines was 2,4,5-trihydroxyphenylethylamine or 6-hydroxydopamine (6-OHDA) that produces a permanent reduction of NA and DA in the CNS 18. Other compounds that more or less selectively destroy catecholamines include DSP-4 19 and MPTP 20. The most frequently used compound to produce catecholamine denervations has been 6-OHDA , and it has been proposed that it undergoes spontaneous autooxidation within neurons to intermediate p-quinones, which then affect membrane integrity or interfere with energy production by interrupting the mitochondrial respiratory chain 21. Compounds that affect 5-HT neurons were developed later, and similar mechanisms of action have been proposed for the most frequently used, i.e.: 5,6-dihydroxytryptamine 22–24 and 5,7-dihydroxytryptamine 25–27. In addition, other neurotoxins for central 5-HT neurons include synthesis inhibitors and amphetamine derivatives and will also be discussed in this review.


Raphe Nucleus Tryptophan Hydroxylase Terminal Field Dopaminergic Neurotoxicity Local Cerebral Glucose Utilization 
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  1. 1.
    Twarog BM, Page IH. Serotonin contents of some mammalian tissues and urine and a method for its determination. J Physiol (Lond) 1953; 175: 157–61.Google Scholar
  2. 2.
    Amin AH, Crawford TBB, Gaddum JH. The distribution of substance P and 5-hydroxytryptamine in the central nervous system of the dog. J Physiol (Lond) 1954; 126: 596–618.Google Scholar
  3. 3.
    Bogdanski DF, Pletscher A, Brodie BB, Udenfriend S. Identification and assay of serotonin in brain. J Pharmacol Exp Ther 1956; 117: 82–8.PubMedGoogle Scholar
  4. 4.
    Zieher LM, De Robertis E. Subcellular localization of 5-hydroxytryptamine in rat brain. Biochem Pharmacol 1963; 12: 596–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Dahlström A, Fuxe K. Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brainstem neurons. Acta Physiol Scand 1964; 62 (suppl): 1–55.Google Scholar
  6. 6.
    Anden N-E, Dahlström A, Fuxe K, Larsson K. Mapping out of catecholamine and 5-hydroxytryptamine neurons innervating the telencephalon and diencephalon. Life Sci 1965; 4: 1275–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Anden N-E, Fuxe K, Ungerstedt U. Monoamine pathways to cerebellum and cerebral cortex. Experientia 1967; 23: 838–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand 1971; 82 (suppl 367): 1–48.Google Scholar
  9. 9.
    Moore RY, Halaris AE, Jones BE. Serotonin neurons of the midbrain raphe: Ascending projections. J Comp Neurol 1978; 180: 417–38.PubMedCrossRefGoogle Scholar
  10. 10.
    Kuhar MJ, Aghajanian GK, Roth RH. Tryptophan hydroxylase activity and synaptosomal uptake of serotonin in discrete brain regions after midbrain raphe lesions: correlations with serotonin levels and histochemical fluorescence. Brain Res 1972; 44: 165–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Steinbusch HWM. Distribution of serotonin-immunoreactivity in the central nervous system of the rat: cell bodies and terminals. Neurosci 1981; 6: 557–618.CrossRefGoogle Scholar
  12. 12.
    Azmitia EF, Segal M. An autoradiographic analysis of the differential projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 1978; 179: 641–68.PubMedCrossRefGoogle Scholar
  13. 13.
    Beaudet A, Descarries L. The fine structure of central serotonin neurons. J Physiol (Paris) 1981; 77: 193–203Google Scholar
  14. 14.
    Parent A, Descarries L, Beaudet A. Organization of ascending serotonin systems in the adult rat brain. A radioautographic study after intraventricular administration of [311]-5-hydroxytryptamine. Neurosci 1981; 6: 115–38.CrossRefGoogle Scholar
  15. 15.
    Descarries L, Audet MA, Doucet G, Garcia S, Oleskevich S, Séguéla P, Soghomonian J-J, Watkins KC. Morphology of central serotonin neurons. Brief review of quantified aspects of their distribution and ultrastructural relationships. Ann NY Acad Sci 1990; 600: 81–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Cannon WB. A law of denervation. Amer J Med Sci 1939: 198: 737–50.CrossRefGoogle Scholar
  17. 17.
    Levi-Montalcini R, Booker B. Destruction of the sympathetic ganglia in mammals by an antiserum to the nerve growth promoting factor. Proc Nat Acad Sci USA 1960; 46: 384–91.PubMedCrossRefGoogle Scholar
  18. 18.
    Thoenen H, Tranzer W. The pharmacology of 6-hydroxydopamine. Ann Rev Pharmacol 1973; 13: 169–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Jonsson G, Wiesel F-A, Hallmam H. Developmental plasticity of central noradrenaline neurons after damage-changes in transmitter functions. J Neurobiol 1979; 10: 337–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine analog synthesis. Science 1983; 219: 979–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Wagner K and Trendelenburg U. Effect of 6-hydroxydopamine on oxidative phosphorylation and on monoamine oxidase activity. Naunyn-Schmiedeberg’s Arch Pharmacol 1971; 269: 110–6.Google Scholar
  22. 22.
    Baumgarten HG, Björklund A, Lachenmayer L, Nobin A, Stenevi U. Long-lasting selective depletion of brain serotonin by 5,6-dihydroxytryptamine. Acta Physiol Scand 1971; 373: 1–16.Google Scholar
  23. 23.
    Costa E, Daly J, Lefevre H, Meck J, Revuelta A, Sparro F, Strada, S, Daly J. Serotonin and catecholamine concentrations in brains of rats injected intracerebrally with 5,6-dihydroxytryptamine. Brain Res 1972; 44: 304–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Daly J, Fuxe K, Jonsson G. Effects of intracerebral injection of 5,6-dihydroxytryptamine on cerebral monoamine neurons: evidence for selective degeneration of central 5-hydroxytryptamine neurons. Brain Res 1973; 49: 476–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Baumgarten HG, Lachenmayer L. 5,7-Dihydroxytryptamine: improvements in chemical lesioning of indoleamine neurons in the mammalian brain. Z. Zellforsh 1972; 135: 399–414.CrossRefGoogle Scholar
  26. 26.
    Daly J, Fuxe K, Jonsson G. 5,7-Dihydroxytryptamine as a tool for the morphological and functional analysis of central 5-hydroxytryptamine neurons. Res Commun Chem Path Pharmacol 1974; 7: 175–87.Google Scholar
  27. 27.
    Baumgarten HG, Klemm HP, Lachenmayer L, Björklund A, Lovenberg W, Schlossberger HG. Mode and mechanism of action of neurotoxic indoleamines. A review and progress report. Ann NY Acad Sci 1978; 305: 3–24.CrossRefGoogle Scholar
  28. 28.
    Baumgarten HG, Björklund A. Neurotoxin indoleamines and monoamine neurons. Ann Rev Pharmacol Toxicol 1976; 16: 101–11.CrossRefGoogle Scholar
  29. 29.
    Reader TA. Neurotoxins that affect central indoleamine neurons. In: Boulton AA, Baker GB, Juorio AV, eds. Drugs as Tools in Neurotransmitter Research. Clifton, New Jersey, USA: Humana Press, 1989: 49–102.CrossRefGoogle Scholar
  30. 30.
    Klemm HP, Baumgarten HG, Schlossberger HG. Polarographic measurements of spontaneous and mitochondria-promoted oxydation of 5,6- and 5,7-dihydroxytryptamine. J Neurochem 1980; 35: 1400–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Klemm HP, Baumgarten HG, Schlossberger HG. Interaction of 5,6- and 5,7-dyhydroxytryptamine with tissue monoamine oxidase. Ann NY Acad Sci 1978; 305: 36–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Klemm HP, Baumgarten HG, Schlossberger HG. In vitro studies on the interaction of brain monoamine oxidase with 5,6- and 5,7-dihydroxytryptamine. J Neurochem 1979; 32: 111–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Sinhababu AK, Ghosh AK, Borchardt RT. Molecular mechanism of action of 5,6-dihydroxytryptamine. Synthesis and biological evaluation of 4-methyl-, 7-methyl-, and 4,7-dimethyl5,6-dihydroxytryptamines. J Med Chem 1985; 28: 1273–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Björklund A, Baumgarten HG, Rensch A. 5,7-dihydroxytryptamine: Improvement of its selectivity for serotonin neurons in the CNS by pretreatment with desipramine. J Neurochem 1975; 24: 833–5.PubMedGoogle Scholar
  35. 35.
    Creveling CR, Lundstrom J, McNeal ET, Tice L, Daly JW. Dihydroxytryptamines: effects on noradrenergic function in mouse heart in vivo. Med Pharmacol 1975; 11: 211–22.Google Scholar
  36. 36.
    Baumgarten HG, Jenner S, Klemm HP. Serotonin neurotoxins: recent advances in the mode of administration and molecular mechanism of action. J Physiol (Paris) 1981; 77: 309–14.Google Scholar
  37. 37.
    Baumgarten HG, Klemm HP, Sievers J, Schlossberger HG. Dihydroxytryptamines as tools to study the neurobiology of serotonin. Brain Res Bull 1982; 9: 131–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Gerson S, Baldessarin RJ. Selective destruction of serotonin terminals in rat forebrain by high doses of 5,7-dihydroxytryptamine. Brain Res 1975; 85: 140–5.CrossRefGoogle Scholar
  39. 39.
    Breese GR, Cooper BR. Behavioral and biochemical interactions of 5,7-dihydroxytryptamine with various drugs when administered intracisternally to adult and developing rats. Brain Res 1975; 98: 517–27.PubMedCrossRefGoogle Scholar
  40. 40.
    Ferron A, Reader TA, Descarries L. Responsiveness of cortical neurons to serotonin after 5,7-DHT denervation of PCPA depletion. J Physiol (Paris) 1981; 77: 381–4.Google Scholar
  41. 41.
    Gauthier P, Reader TA. Adrenomedullary secretory response to midbrain stimulation in rat: effects of depletion on brain catecholamines or serotonin. Can J Physiol Pharmacol 1982; 60: 1464–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Ferron A, Descarries L, Reader TA. Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion. Brain Res 1982; 231: 93–108.PubMedCrossRefGoogle Scholar
  43. 43.
    Reader TA, Gauthier P. Catecholamines and serotonin in the rat central nervous system after 6-OHDA, 5,7-DHT and p-CPA. J Neural Transm 1984; 59: 207–27.PubMedCrossRefGoogle Scholar
  44. 44.
    Mc Rae Deguerce A, Berod A, Keller A, Chouvet G, Joh TH, Pujol J-F. Alterations in tyrosine hydroxylase elicited by raphe nuclei lesions in the rat locus coeruleus: evidence for the involvement of serotonin afferents. Brain Res 1982; 235: 285–301.CrossRefGoogle Scholar
  45. 45.
    Lyness WH, Demarest KT, Moore KE. Effects of d-amphetamine and disruption of 5-hydroxytryptaminergic neuronal systems on the synthesis of dopamine in selected regions of the rat brain Neuropharmacol 1980; 19: 883–9.Google Scholar
  46. 46.
    Koe BK, Weissman A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 1966; 154: 499–516.PubMedGoogle Scholar
  47. 47.
    Miller FP, Cox RHJr, Snodgrass WR, Maickel RP. Comparative effects of p-chlorophenylalanine, p-chloroamphetamine and p-chloro-N-methylamphetamine on rat brain norepinephrine, serotonin and 5-hydroxyindole-3-acetic acid. Biochem Pharmacol 1970; 19: 435–42.PubMedCrossRefGoogle Scholar
  48. 48.
    Reader TA. Catecholamines and serotonin in rat frontal cortex after PCPA and 6-OHDA: absolute amounts and ratios. Brain Res Bull 1982; 8: 527–34.PubMedCrossRefGoogle Scholar
  49. 49.
    Aghajanian GK, Kuhar MJ, Roth RH. Serotonin-containing neuronal perikarya and terminals: differential effects of p-chlorophenylalanine. Brain Res 1973; 54: 85–101.PubMedCrossRefGoogle Scholar
  50. 50.
    Dewar KM, Grondin L, Carli M, Lima L, Reader TA. [3H]Paroxetine binding and serotonin content of rat cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region following p-chlorophenylalanine and p-chloroamphetamine treatment. J Neurochem 1992; 58: 250–7PubMedCrossRefGoogle Scholar
  51. 51.
    Fuller RW, Hines CW, Mills J. Lowering of brain serotonin by chloroamphetamines. Biochem Pharmacol 1965; 14: 483–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Pletscher A, Burkard WP, Bruderer H, Gey KF. Decrease of cerebral 5-hydroxytryptamine and 5-hydroxyindoleacetic acid by an arylalkylamine. Life Sci 1963; 2: 828–33.CrossRefGoogle Scholar
  53. 53.
    Sanders-Bush E, Bushibg IA, Sulser F. Long-term effects of p-chloroamphetamine on tryptophan hydroxylase activity and on the levels of 5-hydroxytryptophan and 5-hydroxyindoleacetic acid in brain. Eur J Pharmacol 1972; 20: 385–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Berger UV, Grzanna R, Molliver ME. Depletion of serotonin using p-chlorophenylalanine (PCPA) and reserpine protects against the neurotoxic effects of p-chloroamphetamine (PCA) in the brain. Exper Neurol 1989; 103: 111–5.CrossRefGoogle Scholar
  55. 55.
    Fishman JB, Rubins JB, Chen IC, Dickey BF, Volicer L. Modification of brain guanine nucleotide-binding regulatory proteins by tryptamine-4,5-dione, a neurotoxic derivative of serotonin. J Neurochem 1991; 56: 1851–4.PubMedCrossRefGoogle Scholar
  56. 56.
    De Souza EB, Battaglia G, Insel TR. Neurotoxic effect of MDMA on brain serotonin neurons: evidence from neurochemical and radioligand binding studies. Ann NY Acad Sci 1990; 600: 682–97.PubMedCrossRefGoogle Scholar
  57. 57.
    McBean DE, Sharkey J, Ritchie IM, Kelly PA. Chronic effects of the selective serotoninergic neurotoxin, methylenedioxyamphetamine, upon cerebral function. Neurosci 1990; 38: 271–5.CrossRefGoogle Scholar
  58. 58.
    Schmidt CJ, Black CK, Abbate GM, Taylor VL. Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors. Brain Res 1990; 529: 85–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Trulson ME, Jacobs BL. Behavioral evidence for the rapid release of CNS serotonin by PCA and fenfluramine. Eur J Pharmacol 1976; 36: 149–54.PubMedCrossRefGoogle Scholar
  60. 60.
    Fuller RW. Pharmacology of central serotonin neurons. Ann Rev Pharmacol Toxicol 1980; 20: 111–127.Google Scholar
  61. 61.
    Dewar KM, Reader TA, Grondin L, Descarries L. [3H]Paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum and midbrain raphe nuclei region. Synapse 1991; 9: 14–26.PubMedCrossRefGoogle Scholar
  62. 62.
    Molliver DC, Molliver ME. Anatomic evidence for a neurotoxic effect of (t)-fenfluramine upon serotonergic projections in the rat. Brain Res 1990; 511: 165–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA. Intraneuronal generation of a pyridinium metabolite may cause drug-induced Parkinsonism. Nature 1984; 311: 464–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Chiba K, Trevor A, Castagnoli N. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 1984; 120: 574–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Heikkila RE, Hess A, Duvoisin RC. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6tetrahydropyridine (MPTP) in mice. Science 1984; 224: 1451–3.PubMedCrossRefGoogle Scholar
  66. 66.
    Heikkila RE, Sonsalla PK, Duvoisin RC. Biochemical models of Parkinson’s disease. In: Boulton AA, Baker GB, Juorio AV, eds. Drugs as Tools in Neurotransmitter Research. Clifton, New Jersey, USA: Humana Press, 1989: 351–84.CrossRefGoogle Scholar
  67. 67.
    Brooks WJ, Jarvis MF, Wagner GC. Astrocytes as a primary locus for the conversion MPTP into MPP+. J Neural Trans 1989; 76: 1–12.CrossRefGoogle Scholar
  68. 68.
    Miyake H, Chiueh CC. Effects of MPP+ on the release of serotonin and 5-hydroxyindoleacetic acid from rat striatum in vivo. Eur J Pharmacol 1989; 166: 49–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Tomás A. Reader
    • 1
  • Karen M. Dewar
    • 1
  1. 1.Centre de recherche en sciences neurologiques, and Centre de recherche psychiatrique Fernand-Séguin Départements de Physiologie et de Psychiatrie Faculté de MédecineUniversité de Montréal MontréalQuébecCanada

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