Cell and Tissue Research

, Volume 318, Issue 1, pp 215–224

Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP

Review

Abstract

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson’s disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common “classical” toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this “special issue.”

Keywords

Parkinson’s disease Animal models MPTP 6-OHDA 

References

  1. Adams JD Jr, Klaidman LK, Leung AC (1993) MPP+ and MPDP+ induced oxygen radical formation with mitochondrial enzymes. Free Radic Biol Med 15:181–186CrossRefPubMedGoogle Scholar
  2. Andrew R, Watson DG, Best SA, Midgley JM, Wenlong H, Petty RK (1993) The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res 18:1175–1177PubMedGoogle Scholar
  3. Bankiewicz KS, Oldfield EH, Chiueh CC, Doppman JL, Jacobowitz DM, Kopin IJ (1986) Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci 39:7–16CrossRefPubMedGoogle Scholar
  4. Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334CrossRefPubMedGoogle Scholar
  5. Ben-Shachar D, Youdim MB (1991) Intranigral iron injection induces behavioral and biochemical “parkinsonism” in rats. J Neurochem 57:2133–2135PubMedGoogle Scholar
  6. Berger K, Przedborski S, Cadet JL (1991) Retrograde degeneration of nigrostriatal neurons induced by intrastriatal 6-hydroxydopamine injection in rats. Brain Res Bull 26:301–307CrossRefPubMedGoogle Scholar
  7. Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bioessays 24:308–318CrossRefPubMedGoogle Scholar
  8. Bezard E, Imbert C, Deloire X, Bioulac B, Gross CE (1997a) A chronic MPTP model reproducing the slow evolution of Parkinson’s disease: evolution of motor symptoms in the monkey. Brain Res 766:107–112CrossRefPubMedGoogle Scholar
  9. Bezard E, Dovero S, Bioulac B, Gross CE (1997b) Kinetics of nigral degeneration in a chronic model of MPTP-treated mice. Neurosci Lett 234:47–50CrossRefPubMedGoogle Scholar
  10. Bezard E, Gross CE, Fournier MC, Dovero S, Bloch B, Jaber M (1999) Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol 155:268–273CrossRefPubMedGoogle Scholar
  11. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65:135–172CrossRefPubMedGoogle Scholar
  12. Cadet JL, Katz M, Jackson-Lewis V, Fahn S (1989) Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: behavioral and biochemical evidence. Brain Res 476:10–15CrossRefPubMedGoogle Scholar
  13. Carlsson A, Lindquist M, Magnusson T (1957) 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180:1200Google Scholar
  14. Cenci MA, Whishaw IQ, Schallert T (2002) Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci 3:574–579CrossRefPubMedGoogle Scholar
  15. Cleeter MW, Cooper JM, Schapira AH (1992) Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. J Neurochem 58:786–789PubMedGoogle Scholar
  16. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909CrossRefPubMedGoogle Scholar
  17. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1:249–254CrossRefPubMedGoogle Scholar
  18. Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426PubMedGoogle Scholar
  19. Del Zompo M, Piccardi MP, Ruiu S, Quartu M, Gessa GL, Vaccari A (1993) Selective MPP+ uptake into synaptic dopamine vesicles: possible involvement in MPTP neurotoxicity. Br J Pharmacol 109:411–414PubMedGoogle Scholar
  20. Faull RL, Laverty R (1969) Changes in dopamine levels in the corpus striatum following lesions in the substantia nigra. Exp Neurol 23:332–340CrossRefPubMedGoogle Scholar
  21. Forno LS, Langston JW, DeLanney LE, Irwin I, Ricaurte GA (1986) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 20:449–455PubMedGoogle Scholar
  22. Forno LS, DeLanney LE, Irwin I, Langston JW (1993) Similarities and differences between MPTP-induced parkinsonism and Parkinson’s disease. Neuropathologic considerations. Adv Neurol 60:600–608PubMedGoogle Scholar
  23. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380:252–255CrossRefPubMedGoogle Scholar
  24. Gee P, San RH, Davison AJ, Stich HF (1992) Clastogenic and mutagenic actions of active species generated in the 6-hydroxydopamine/oxygen reaction: effects of scavengers of active oxygen, iron, and metal chelating agents. Free Radic Res Commun 16:1–10PubMedGoogle Scholar
  25. Gerlach M, Riederer P (1996) Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm Suppl 103:987–1041Google Scholar
  26. Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P (2003) Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 9:589–895CrossRefPubMedGoogle Scholar
  27. Giovanni A, Sieber BA, Heikkila RE, Sonsalla PK (1994a) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1. Systemic administration. J Pharmacol Exp Ther 270:1000–1007PubMedGoogle Scholar
  28. Giovanni A, Sonsalla PK, Heikkila RE (1994b) Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2. Central administration of 1-methyl-4-phenylpyridinium. J Pharmacol Exp Ther 270:1008–1014PubMedGoogle Scholar
  29. Glinka Y, Gassen M, Youdim MB (1997) Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm Suppl 50:55–66PubMedGoogle Scholar
  30. Grondin R, Zhang Z, Ai Y, Gash DM, Gerhardt GA (2003) Intracranial delivery of proteins and peptides as a therapy for neurodegenerative diseases. Prog Drug Res 61:101–123PubMedGoogle Scholar
  31. Hasegawa E, Takeshige K, Oishi T, Murai Y, Minakami S (1990) 1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles. Biochem Biophys Res Commun 170:1049–1055PubMedGoogle Scholar
  32. Hefti F, Melamed E, Wurtman RJ (1980) Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res 195:123–137CrossRefPubMedGoogle Scholar
  33. Hirsch EC, Hoglinger G, Rousselet E, Breidert T, Parain K, Feger J, Ruberg M, Prigent A, Cohen-Salmon C, Launay JM (2003) Animal models of Parkinson’s disease in rodents induced by toxins: an update. J Neural Transm Suppl 65:89–100PubMedGoogle Scholar
  34. Hoffer BJ, Hoffman A, Bowenkamp K, Huettl P, Hudson J, Martin D, Lin LF, Gerhardt GA (1994) Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo. Neurosci Lett 182:107–111CrossRefPubMedGoogle Scholar
  35. Hudson J, Granholm AC, Gerhardt GA, Henry MA, Hoffman A, Biddle P, Leela NS, Mackerlova L, Lile JD, Collins F, Hoffer BJ (1995) Glial cell line-derived neurotrophic factor augments midbrain dopaminergic circuits in vivo. Brain Res Bull 36:425–432CrossRefPubMedGoogle Scholar
  36. Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S (1995) Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 4:257–269CrossRefPubMedGoogle Scholar
  37. Javitch JA, Snyder SH (1984) Uptake of MPP(+) by dopamine neurons explains selectivity of parkinsonism-inducing neurotoxin, MPTP. Eur J Pharmacol 106:455–456CrossRefPubMedGoogle Scholar
  38. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82:2173–2177PubMedGoogle Scholar
  39. Jeon BS, Jackson-Lewis V, Burke RE (1995) 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4:131–137CrossRefPubMedGoogle Scholar
  40. Kirik D, Georgievska B, Bjorklund A (2004) Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci 7:105–110CrossRefPubMedGoogle Scholar
  41. Klaidman LK, Adams JD Jr, Leung AC, Kim SS, Cadenas E (1993) Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase. Free Radic Biol Med 15:169–179CrossRefPubMedGoogle Scholar
  42. Knoll J (1986) The pharmacology of (−)deprenyl. J Neural Transm Suppl 22:75–89PubMedGoogle Scholar
  43. Kopin IJ, Markey SP (1988) MPTP toxicity: implications for research in Parkinson’s disease. Annu Rev Neurosci 11:81–96CrossRefPubMedGoogle Scholar
  44. Kumar R, Agarwal AK, Seth PK (1995) Free radical-generated neurotoxicity of 6-hydroxydopamine. J Neurochem 64:1703–1707PubMedGoogle Scholar
  45. Langston JW, Ballard PA Jr (1983) Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med 309:310Google Scholar
  46. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980PubMedGoogle Scholar
  47. Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D (1999) Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 46:598–605CrossRefPubMedGoogle Scholar
  48. Lindner M, Cai, CK, Plone MA, Frydel BR, Blaney TJ, Emerich DF, Hoane MR (1999) Incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine produce akinesia, rigidity, tremor and cognitive deficits in middle-aged rats. Behav Brain Res 102:1–16CrossRefPubMedGoogle Scholar
  49. Liu Y, Peter D, Roghani A, Schuldiner S, Prive GG, Eisenberg D, Brecha N, Edwards RH (1992) A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 70:539–551CrossRefPubMedGoogle Scholar
  50. Luthman J, Fredriksson A, Sundstrom E, Jonsson G, Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res 33:267–277PubMedGoogle Scholar
  51. Mayer RA, Kindt MV, Heikkila RE (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J Neurochem 47:1073–1079PubMedGoogle Scholar
  52. Mizuno Y, Sone N, Saitoh T (1987) Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on activities of the enzymes in the electron transport system in mouse brain. J Neurochem 48:1787–1793PubMedGoogle Scholar
  53. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36:2503–2508CrossRefPubMedGoogle Scholar
  54. Nicklas WJ, Youngster SK, Kindt MV, Heikkila RE (1987) MPTP, MPP+ and mitochondrial function. Life Sci 40:721–729CrossRefPubMedGoogle Scholar
  55. Nieoullon A, Cheramy A, Glowinski J (1977) Interdependence of the nigrostriatal dopaminergic systems on the two sides of the brain in the cat. Science 198:416–418PubMedGoogle Scholar
  56. Orth M, Tabrizi SJ (2003) Models of Parkinson’s disease. Mov Disord 18:729–737CrossRefPubMedGoogle Scholar
  57. Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS (1989) A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res 494:285–293CrossRefPubMedGoogle Scholar
  58. Perumal AS, Gopal VB, Tordzro WK, Cooper TB, Cadet JL (1992) Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain. Brain Res Bull 29:699–701CrossRefPubMedGoogle Scholar
  59. Périer C, Agid Y, Hirsch EC, Feger J (2000) Ipsilateral and contralateral subthalamic activity after unilateral dopaminergic lesion. Neuroreport 11:3275–3278PubMedGoogle Scholar
  60. Petzinger GM, Langston JW (1998) The MPTP-lesioned non human primate: a model in Parkinson’s disease. In: Marwah J, Teitelbaum H (eds) Advances in neurodegenerative disorders. Parkinson’s disease. Prominent, Scottsdale, pp 113–148Google Scholar
  61. 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 140:308–316PubMedGoogle Scholar
  62. 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 150:17–22PubMedGoogle Scholar
  63. Przedborski S, Vila M (2003) The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 991:189–198PubMedGoogle Scholar
  64. Przedborski S, Jackson-Lewis V, Popilskis S, Kostic V, Levivier M, Fahn S, Cadet JL (1991) Unilateral MPTP-induced parkinsonism in monkeys. A quantitative autoradiographic study of dopamine D1 and D2 receptors and re-uptake sites. Neurochirurgie 37:377–382PubMedGoogle Scholar
  65. Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, Togasaki DM (1995) Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67:631–647CrossRefPubMedGoogle Scholar
  66. Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, Akram M (2001) The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76:1265–1274CrossRefPubMedGoogle Scholar
  67. Ramsay RR, Singer TP (1986) Energy-dependent uptake of N-methyl-4-phenylpyridinium, the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, by mitochondria. J Biol Chem 261:7585–7587PubMedGoogle Scholar
  68. Reinhard JF Jr, Diliberto EJ Jr, Viveros OH, Daniels AJ (1987) Subcellular compartmentalization of 1-methyl-4-phenylpyridinium with catecholamines in adrenal medullary chromaffin vesicles may explain the lack of toxicity to adrenal chromaffin cells. Proc Natl Acad Sci USA 84:8160–8164PubMedGoogle Scholar
  69. Sachs C, Jonsson G (1975) Mechanisms of action of 6-hydroxydopamine. Biochem Pharmacol 24:1–8CrossRefPubMedGoogle Scholar
  70. Salin P, Hajji MD, Kerkerian-le Goff L (1996) Bilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway reproduces the effects of unilateral lesion on substance P but not on enkephalin expression in rat basal ganglia. Eur J Neurosci 8:1746–1757PubMedGoogle Scholar
  71. Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415CrossRefPubMedGoogle Scholar
  72. Schmidt N, Ferger B (2001) Neurochemical findings in the MPTP model of Parkinson’s disease. J Neural Transm 108:1263–1282CrossRefPubMedGoogle Scholar
  73. Schneider JS, Roeltgen DP (1993) Delayed matching-to-sample, object retrieval, and discrimination reversal deficits in chronic low dose MPTP-treated monkeys. Brain Res 615:351–354CrossRefPubMedGoogle Scholar
  74. Schneider JS, Tinker JP, Van Velson M, Menzaghi F, Lloyd GK (1999) Nicotinic acetylcholine receptor agonist SIB-1508Y improves cognitive functioning in chronic low-dose MPTP-treated monkeys. J Pharmacol Exp Ther 290:731–739PubMedGoogle Scholar
  75. Schwarting RK, Huston JP (1996) The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 50:275–331CrossRefPubMedGoogle Scholar
  76. Senoh S, Witkop B (1959) Non-enzymatic conversions of dopamine to norepinephrine and trihydroxyphenetylamines. J Am Chem Soc 81:6222–6231Google Scholar
  77. Senoh S, Creveling CR, Udenfriend S, Witkop B (1959) Chemical, enzymatic, and metabolic studies on the mechanism of oxidation of dopamine. J Am Chem Soc 81:6236–6240Google Scholar
  78. Song DD, Shults CW, Sisk A, Rockenstein E, Masliah E (2004) Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol 186:158–172CrossRefPubMedGoogle Scholar
  79. Sonsalla PK, Heikkila RE (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur J Pharmacol 129:339–345CrossRefPubMedGoogle Scholar
  80. Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson-Lewis V, Przedborski S, Uhl GR (1997) VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci USA 94:9938–9943CrossRefPubMedGoogle Scholar
  81. Tatton NA, Kish SJ (1997) In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience 77:1037–1048CrossRefPubMedGoogle Scholar
  82. Thoenen H (1972) Surgical, immunological and chemical sympathectomy. Their application in the investigation of the physiology and pharmacology of the sympathetic nervous system. In: Blaschko H, Muscholl E (eds) Catecholamines. Springer, Berlin Heidelberg New York, pp 813–844 (Chapter 18)Google Scholar
  83. Thoenen H, Tranzer JP (1968) Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmiedeberg’s Arch Exp Pathol Pharmacol 261:271–288PubMedGoogle Scholar
  84. Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L (1995) Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373:335–339CrossRefPubMedGoogle Scholar
  85. Tranzer JP, Thoenen H (1968) An electron microscopic study of selective, acute degeneration of sympathetic nerve terminals after administration of 6-hydroxydopamine. Experientia 24:155–156PubMedGoogle Scholar
  86. Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central dopamine neurons. Eur J Pharmacol 5:107–110CrossRefPubMedGoogle Scholar
  87. Ungerstedt U (1976) 6-Hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway: the turning syndrome. Pharmacol Ther 2:37–40CrossRefGoogle Scholar
  88. Unsicker K (1996) GDNF: a cytokine at the interface of TGF-betas and neurotrophins. Cell Tissue Res 286:175–178CrossRefPubMedGoogle Scholar
  89. Unsicker K, Chamley JH, McLean J (1976a) Extraneuronal effects of 6-hydroxydopamine. Tissue culture studies on adrenocortical cells of rats. Cell Tissue Res 174:83–97PubMedGoogle Scholar
  90. Unsicker K, Allan IJ, Newgreen DF (1976b) Extraneuronal effects of 6-hydroxydopamine and extraneuronal uptake of noradrenaline. In-vivo and in-vitro studies on adrenocortical cells of lizards and rats. Cell Tissue Res 173:45–69PubMedGoogle Scholar
  91. Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of Neuroanatomy and IZNUniversity of HeidelbergHeidelbergGermany

Personalised recommendations