Skip to main content
SpringerLink
Log in

Perinatal Lesioning and Lifelong Effects of the Noradrenergic Neurotoxin 6-Hydroxydopa

  • Chapter
  • First Online:
Neurotoxin Modeling of Brain Disorders—Life-long Outcomes in Behavioral Teratology

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 29))

Abstract

6-hydroxydopa (6-OHDOPA) was synthesized with the expectation that it would be able to cross the blood–brain barrier to be enzymatically decarboxylated to 6-hydroxydopamine (6-OHDA), the newly discovered neurotoxin for noradrenergic and dopaminergic neurons. In part, 6-OHDOPA fulfilled these criteria. When administered experimentally to rodents, 6-OHDOPA destroyed peripheral sympathetic noradrenergic nerves and did exert neurotoxicity to noradrenergic nerves in brain—in large part, from its conversion to 6-OHDA. However, the efficacy of 6-OHDOPA was less than that of 6-OHDA; also, 6-OHDOPA was relatively selective for noradrenergic neurons; near-lethal doses of 6-OHDOPA were required to damage dopaminergic nerves; and ultimately, 6-OHDOPA was found to be an agonist at AMPA receptors, thus accounting for more non-specificity. Nevertheless, 6-OHDOPA was found to be a particularly valuable tool in uncovering processes and mechanisms associated with noradrenergic nerve regeneration and sprouting, particularly when administered to perinatal rodents. Also, 6-OHDOPA was a good tool for selective mapping of noradrenergic nerve tracts in brain, since dopaminergic tracts were unaffected and did not interfere with the histofluorescent methodology used for this purpose in the early 1970s. As an experimental research tool, 6-OHDOPA was valuable in a short time-window, but its utility is largely limited because of newer research technologies that provide better means today for nerve tract mapping, and for experimental approaches engaged toward study of processes and mechanisms attending nerve regeneration. AMPA actions of 6-OHDOPA have not been extensively studied, so this avenue may enliven use of 6-OHDOPA in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adams RN, Murrill E, McCreery R, Blank L, Karolczak M (1972) 6-Hydroxydopamine, a new oxidation mechanism. Eur J Pharmacol 17(2):287–292

    Article  CAS  Google Scholar 

  • Agrup G, Hansson C, Rorsman H, Rosengren E, Tegner E (1983) Methaemoglobin-catalysed formation of dopa and 6-OH-dopa from tyrosine. Acta Derm Venereol 63(2):152–155

    CAS  PubMed  Google Scholar 

  • Aizenman E, White WF, Loring RH, Rosenberg PA (1990) A 3,4-dihydroxyphenylalanine oxidation product is a non-N-methyl-D-aspartate glutamatergic agonist in rat cortical neurons. Neurosci Lett 116(1–2):168–171

    Article  CAS  Google Scholar 

  • Aizenman E, Boeckman FA, Rosenberg PA (1992) Glutathione prevents 2,4,5-trihydroxyphenylalanine excitotoxicity by maintaining it in a reduced, non-active form. Neurosci Lett 144(1–2):233–236

    Article  CAS  Google Scholar 

  • Berkowitz BA, Spector S, Brossi A, Focella A, Teitel S (1970) Preparation and biological properties of (−)- and (+)-6-hydroxydopa. Experientia 26(9):982–983

    Article  CAS  Google Scholar 

  • Biscoe TJ, Evans RH, Headley PM, Martin MR, Watkins JC (1976) Structure-activity relations of excitatory amino acids on frog and rat spinal neurones. Br J Pharmacol 58(3):373–382

    Article  CAS  Google Scholar 

  • Blank CL, Kissinger PT, Adams RN (1972) 5,6-Dihydroxyindole formation from oxidized 6-hydroxydopamine. Eur J Pharmacol 19(3):391–394

    Article  CAS  Google Scholar 

  • Cha JH, Dure LS IV, Sakurai SY, Penney JB, Young AB (1991) 2,4,5-Trihydroxyphenylalanine (6-hydroxy-dopa) displaces [3H]AMPA binding in rat striatum. Neurosci Lett 132(1):55–58

    Article  CAS  Google Scholar 

  • Clark MB, King JC, Kostrzewa RM (1979) Loss of nerve cell bodies in caudal locus coeruleus following treatment of neonates with 6-hydroxydopa. Neurosci Lett 13(3):331–336

    Article  CAS  Google Scholar 

  • Cohen G, Heikkila RE (1974) The generation of hydrogen peroxide, superoxide radical, and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic agents. J Biol Chem 249(8):2447–2452

    CAS  PubMed  Google Scholar 

  • Corrodi H, Clark WG, Masuoka DI (1971) The synthesis and effects of DL-6-hydroxydopa. In: Malmfors T, Thoenen H (eds) 6-Hydroxydopamine and catecholamine neurons. North Holland, Amsterdam, pp 187–192

    Google Scholar 

  • Evans JM, Cohen G (1989) Studies on the formation of 6-hydroxydopamine in mouse brain after administration of 2,4,5-trihydroxyphenylalanine (6-hydroxyDOPA). J Neurochem 52(5):1461–1467

    Article  CAS  Google Scholar 

  • Evans J, Cohen G (1993) Catecholamine uptake inhibitors elevate 6-hydroxydopamine in brain after administration of 6-hydroxydopa. Eur J Pharmacol 232(2–3):241–245

    Article  CAS  Google Scholar 

  • Harston CT, Morrow A, Kostrzewa RM (1980) Enhancement of sprouting and putative regeneration of central noradrenergic fibers by morphine. Brain Res Bull 5(4):421–424

    Article  CAS  Google Scholar 

  • Harston CT, Clark MB, Hardin JC, Kostrzewa RM (1981) Opiate-enhanced toxicity and noradrenergic sprouting in rats treated with 6-hydroxydopa. Eur J Pharmacol 71(4):365–373

    Article  CAS  Google Scholar 

  • Heikkila R, Cohen G (1971) Inhibition of biogenic amine uptake by hydrogen peroxide: a mechanism for toxic effects of 6-hydroxydopamine. Science 172(3989):1257–1258

    Article  CAS  Google Scholar 

  • Heikkila R, Cohen G (1972a) Further studies on the generation of hydrogen peroxide by 6-hydroxydopamine. Potentiation by ascorbic acid. Mol Pharmacol 8(2):241–248

    CAS  PubMed  Google Scholar 

  • Heikkila RE, Cohen G (1972b) In vivo generation of hydrogen peroxide from 6-hydroxydopamine. Experientia 28(10):1197–1198

    Article  CAS  Google Scholar 

  • Heikkila RE, Cohen G (1973) 6-Hydroxydopamine: evidence for superoxide radical as an oxidative intermediate. Science 181(4098):456–457

    Article  CAS  Google Scholar 

  • Jacobowitz D, Kostrzewa R (1971) Selective action of 6-hydroxydopa on noradrenergic terminals: mapping of preterminal axons of the brain. Life Sci I 10(23):1329–1342

    Article  CAS  Google Scholar 

  • Jaim-Etcheverry G, Zieher LM (1977) Differential effect of various 6-hydroxydopa treatments on the development of central and peripheral noradrenergic neurons. Eur J Pharmacol 45(2):105–116

    Article  CAS  Google Scholar 

  • Jaim-Etcheverry G, Teitelman G, Zieher LM (1975) Choline acetyltransferase activity increases in the brain stem of rats treated at birth with 6-hydroxydopa. Brain Res 100(3):699–704

    Article  CAS  Google Scholar 

  • Jonsson G, Sachs C (1973) Pharmacological modifications of the 6-hydroxy-dopa induced degeneration of central noradrenaline neurons. Biochem Pharmacol 22(14):1709–1716

    Article  CAS  Google Scholar 

  • Klisans-Fuenmayor D, Harston CT, Kostrzewa RM (1986) Alterations in noradrenergic innervation of the brain following dorsal bundle lesions in neonatal rats. Brain Res Bull 16(1):47–54

    Article  CAS  Google Scholar 

  • Kostrezewa RM, Klara JW, Robertson J, Walker LC (1978) Studies on the mechanism of sprouting of noradrenergic terminals in rat and mouse cerebellum after neonatal 6-hydroxydopa. Brain Res Bull 3(5):525–531

    Article  CAS  Google Scholar 

  • Kostrzewa RM (1975) Effects of neonatal 6 hydroxydopa treatment on monamine content of rat brain and peripheral tissues. Res Commun Chem Pathol Pharmacol 11(4):567–579

    CAS  PubMed  Google Scholar 

  • Kostrzewa RM (1988) Reorganization of noradrenergic neuronal systems following neonatal chemical and surgical injury. Prog Brain Res 73:405–423. Review. PMID: 3138742

    Google Scholar 

  • Kostrzewa RM (1998) 6-Hydroxydopa, a catecholamine neurotoxin and endogenous excitotoxin at non-NMDA receptors. In: Kostrzewa RM (ed) Highly selective neurotoxins: basic and clinical applications. Humana Press, Totowa NJ, pp 109–129

    Chapter  Google Scholar 

  • Kostrzewa RM (2007) The blood-brain barrier for catecholamines—revisited. Neurotoxicity Res 11:261–271

    Article  CAS  Google Scholar 

  • Kostrzewa RM (2014) Survey of selective neurotoxins, in Section on Selective Neurotoxins, In: Kostrzewa RM (ed) Handbook of neurotoxicity, Springer New York, Heidelberg, Dordrecht, London, pp 3–67. ISBN 978-1-4614-5835-7 (print); ISBN 978-1-4614-5836-4 (eBook); ISBN 978-1-4614-7458-6 (print and electronic bundle). doi:10.1007/978-1-4614-5836-4_53

    Google Scholar 

  • Kostrzewa RM, Garey RE (1976) Effects of 6-hydroxydopa on noradrenergic neurons in developing rat brain. J Pharmacol Exp Ther 197:105–118

    CAS  PubMed  Google Scholar 

  • Kostrzewa RM, Garey RE (1977) Sprouting of noradrenergic terminals in rat cerebellum following neonatal treatment with 6-hydroxydopa. Brain Res 124:385–391

    Article  CAS  Google Scholar 

  • Kostrzewa RM, Harper JW (1974) Effect of 6-hydroxydopa on catecholamine-containing neurons in brains of newborn rats. Brain Res 69(1):174–181

    Article  CAS  Google Scholar 

  • Kostrzewa RM, Harper JW (1975) Comparison of the neonatal effects of 6-hydroxydopa and 6-hydroxydopamine on growth and development of noradrenergic neurons in the central nervous system, In: Jonsson G, Malmfors T, Sachs C (eds) Chemical tools in catecholamine research, vol I. North Holland Publ Co, Amsterdam, The Netherlands, pp 181–188

    Google Scholar 

  • Kostrzewa R, Jacobowitz D (1972) The effect of 6-hydroxydopa on peripheral adrenergic neurons. J Pharmacol Exp Ther 183(2):284–297

    CAS  PubMed  Google Scholar 

  • Kostrzewa R, Jacobwitz D (1973) Acute effects of 6-hydroxydopa on central monoaminergic neurons. Eur J Pharmacol 21(1):70–80

    Article  CAS  Google Scholar 

  • Kostrzewa RM, Jacobowitz DM (1974) Pharmacological actions of 6-hydroxydopamine. Pharmacol Rev 26(3):199–288. Review. PMID: 4376244

    Google Scholar 

  • Kostrzewa RM, Klisans-Fuenmayor D (1984) Development of an opioid-specific action of morphine in modifying recovery of neonatally-damaged noradrenergic fibers in rat brain. Res Commun Chem Pathol Pharmacol 46(1):3–11

    CAS  PubMed  Google Scholar 

  • Kostrzewa RM, Harston CT, Fukushima H, Brus R (1982) Noradrenergic fiber sprouting in the cerebellum. Brain Res Bull 9(1-6):509-517. PMID: 7172038

    Article  CAS  Google Scholar 

  • Kostrzewa RM, Hardin JC, Jacobowitz DM (1988) Destruction of cells in the midportion of the locus coeruleus by a dorsal bundle lesion in neonatal rats. Brain Res 442(2):321–328

    Article  CAS  Google Scholar 

  • Kostrzewa RM, Kostrzewa JP, Brus R (2000) Dopaminergic denervation enhances susceptibility to hydroxyl radicals in rat neostriatum. Amino Acids 19(1):183–199

    Article  CAS  Google Scholar 

  • Künig G, Hartmann J, Niedermeyer B, Deckert J, Ransmayr G, Heinsen H, Beckmann H, Riederer P (1994a) Excitotoxins L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4,6-trihydroxyphenylalanine (6-OH-DOPA) inhibit [3H] alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) binding in human hippocampus. Neurosci Lett 169(1–2):219–222

    Article  Google Scholar 

  • Künig G, Niedermeyer B, Krause F, Hartmann J, Deckert J, Ransmayr G, Heinsen H, Beckmann H, Riederer P (1994b) Interactions of neurotoxins with non-NMDA glutamate receptors: an autoradiographic study. J Neural Transm Suppl 43:59–62

    PubMed  Google Scholar 

  • Lin JY, Mai LM, Pan JT (1993) Effects of systemic administration of 6-hydroxydopamine, 6-hydroxydopa and 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP) on tuberoinfundibular dopaminergic neurons in the rat. Brain Res 624(1–2):126–130

    Article  CAS  Google Scholar 

  • McLean JH, Kostrzewa RM, May JG (1976) Behavioral and biochemical effects of neonatal treatment of rats with 6-hydroxydopa. Pharmacol Biochem Behav 4(5):601–607

    Article  CAS  Google Scholar 

  • McLean JH, Glasser RS, Kostrzewa RM, May JG (1980) Effects of neonatal 6-hydroxydopa on behavior in female rats. Pharmacol Biochem Behav 13(6):863–868

    Article  CAS  Google Scholar 

  • Morgan DN, McLean JH, Kostrzewa RM (1979) Effects of 6-hydroxydopamine and 6-hydroxydopa on development of behavior. Pharmacol Biochem Behav 11(3):309–312

    Article  CAS  Google Scholar 

  • Nomura Y, Segawa T (1979) Striatal dopamine content reduced in developing rats treated with 6-hydroxydopa. Jpn J Pharmacol 29(2):306–309

    Article  CAS  Google Scholar 

  • Nomura Y, Kajiyama H, Segawa T (1979) Decrease in muscarinic cholinergic response of the rat heart following treatment with 6-hydroxydopa. Eur J Pharmacol 60(4):323–327

    Article  CAS  Google Scholar 

  • Olney JW, Zorumski CF, Stewart GR, Price MT, Wang GJ, Labruyere J (1990) Excitotoxicity of L-dopa and 6-OH-dopa: implications for Parkinson’s and Huntington’s diseases. Exp Neurol 108(3):269–272

    Article  CAS  Google Scholar 

  • Ong HH, Creveling CR, Daly JW (1969) The synthesis of 2,4,5-trihydroxyphenylalanine (6-hydroxydopa). A centrally active norepinephrine-depleting agent. J Med Chem 12(3):458–462

    Article  CAS  Google Scholar 

  • Porter CC, Totaro JA, Stone CA (1963) Effect of 6-hydroxydopamine and some other compounds on the concentration of norepinephrine in the hearts of mice. J Pharmacol Exp Ther 140:308–316

    CAS  PubMed  Google Scholar 

  • Porter CC, Totaro JA, Burcin A (1965) The relationship between radioactivity and norepinephrine concentrations in the brains and hearts of mice following administration of labeled methyldopa or 6-hydroxydopamine. J Pharmacol Exp Ther 150(1):17–22

    CAS  PubMed  Google Scholar 

  • Richardson JS, Jacobowitz DM (1973) Depletion of brain norepinephrine by intraventricular injection of 6-hydroxydopa: a biochemical, histochemical and behavioral study in rats. Brain Res 58(1):117–133

    Article  CAS  Google Scholar 

  • Richardson JS, Cowan N, Hartman R, Jacobowitz DM (1974) On the behavioral and neurochemical actions of 6-hydroxydopa and 5,6-dihydroxytryptamine in rats. Res Commun Chem Pathol Pharmacol 8(1):29–44

    CAS  PubMed  Google Scholar 

  • Rosenberg PA, Loring R, Xie Y, Zaleskas V, Aizenman E (1991) 2,4,5-trihydroxyphenylalanine in solution forms a non-N-methyl-D-aspartate glutamatergic agonist and neurotoxin. Proc Natl Acad Sci USA 88(11):4865–4869

    Article  CAS  Google Scholar 

  • Sachs C, Jonsson G (1972a) Degeneration of central and peripheral noradrenaline neurons produced by 6-hydroxy-DOPA. J Neurochem 19(6):1561–1575

    Article  CAS  Google Scholar 

  • Sachs C, Jonsson G (1972b) Selective 6-hydroxy-DOPA induced degeneration of central and peripheral noradrenaline neurons. Brain Res 40(2):563–568

    Article  CAS  Google Scholar 

  • Sachs C, Jonsson G, Fuxe K (1973) Mapping of central noradrenaline pathways with 6-hydroxy-DOPA. Brain Res 63:249–261

    Article  CAS  Google Scholar 

  • Saner A, Thoenen H (1971) Model experiments on the molecular mechanism of action of 6-hydroxydopamine. Mol Pharmacol 7(2):147–154

    CAS  PubMed  Google Scholar 

  • Senoh S, Witkop B (1959) Formation and rearrangements of aminochromes from a new metabolite of dopamine and some of its derivatives. J Am Chem Soc 81:6231–6235

    Article  CAS  Google Scholar 

  • Thoenen H, Tranzer JP (1968a) Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-Hydroxydopamine. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 261(3):271–288

    Article  CAS  Google Scholar 

  • Thoenen H, Tranzer JP (1968b) On the possibility of chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine (6-OH-DA). Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 260(2):212–213. German. PMID: 4239240

    Google Scholar 

  • Tohyama M, Maeda T, Kashiba A, Shimizu N (1974) Fluorescence and electron microscopic analysis of axonal change of coerulo-cortical noradrenaline neuron system following destruction of locus coeruleus and administration of 6-hydroxydopa in the rat brain. Med J Osaka Univ 24(4):205–221

    CAS  PubMed  Google Scholar 

  • Toyama M, Maeda T, Shimizu N (1974) Detailed noradrenaline pathways of locus coeruleus neuron to the cerebral cortex with use of 6-hydroxydopa. Brain Res 79(1):139–144

    Article  CAS  Google Scholar 

  • Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5(1):107–110

    Article  CAS  Google Scholar 

  • Wehrli PA, Pigott F, Fischer U, Kaiser A (1972) Oxidation products of 6-hydroxy-dopamine. Helv Chim Acta 55(8):3057–3061 (Article in German)

    Article  CAS  Google Scholar 

  • Zieher LM, Jaim-Etcheverry G (1973) Regional differences in the long-term effect of neonatal 6-hydroxydopa treatment on rat brain noradrenaline. Brain Res 60(1):199–207

    Article  CAS  Google Scholar 

  • Zieher LM, Jaim-Etcheverry G (1975a) 6-hydroxydopa during development of central adrenergic neurons produces different long-term changes in rat brain noradrenaline. Brain Res 86(2):271–281

    Article  CAS  Google Scholar 

  • Zieher LM, Jaim-Etcheverry G (1975b) Different alterations in the development of the noradrenergic innervation of the cerebellum and the brain stem produced by neonatal 6-hydroxydopa. Life Sci 17(6):987–991

    Article  CAS  Google Scholar 

  • Zieher LM, Jaim-Etcheverry G (1979) 6-Hydroxydopamine during development: relation between opposite regional changes in brain noradrenaline. Eur J Pharmacol 58(3):217-223. PMID: 510355

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Studies for this paper were provided by the National Institutes of Mental Health; NINDS; March of Dimes; and Scottish Rite Foundation.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, PO Box 70577, Johnson City, TN, 37614, USA

    Richard M. Kostrzewa

Authors
  1. Richard M. Kostrzewa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard M. Kostrzewa .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

  2. Department of Psychology, University of Gothenburg, Gothenburg, Sweden

    Trevor Archer

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Kostrzewa, R.M. (2015). Perinatal Lesioning and Lifelong Effects of the Noradrenergic Neurotoxin 6-Hydroxydopa. In: Kostrzewa, R.M., Archer, T. (eds) Neurotoxin Modeling of Brain Disorders—Life-long Outcomes in Behavioral Teratology. Current Topics in Behavioral Neurosciences, vol 29. Springer, Cham. https://doi.org/10.1007/7854_2015_414

Download citation

Publish with us

Policies and ethics

Search

Navigation