Neurotoxicity Research

, Volume 11, Issue 3–4, pp 151–167 | Cite as

The 6-Hydroxydopamine model of parkinson’s disease

  • Nicola Simola
  • Micaela Morelli
  • Anna R. Carta


The neurotoxin 6-hydroxydopamine (6-OHDA) continues to constitute a valuable topical tool used chiefly in modeling Parkinson’s disease in the rat. The classical method of intracerebral infusion of 6-OHDA, involving a massive destruction of nigrostriatal dopaminergic neurons, is largely used to investigate motor and biochemical dysfunctions in Parkinson’s disease. Subsequently, more subtle models of partial dopaminergic degeneration have been developed with the aim of revealing finer motor deficits. The present review will examine the main features of 6-OHDA models, namely the mechanisms of neurotoxin-induced neurodegeneration as well as several behavioural deficits and motor dysfunctions, including the priming model, modeled by this means. An overview of the most recent morphological and biochemical findings obtained with the 6-OHDA model will also be provided, particular attention being focused on the newly investigated intracellular mechanisms at the striatal level (e.g., A2A and NMDA receptors, PKA, CaMKII, ERK kinases, as well as immediate early genes, GAD67 and peptides). Thanks to studies performed in the 6-OHDA model, all these mechanisms have now been hypothesised to represent the site of pathological dysfunction at cellular level in Parkinson’s disease.


Parkinson’s disease 6-Hydroxydopamine Neurotoxin Dopaminergic neurons Neurodegeneration Priming Behavioural model Neuroadaptive changes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Amalric M, H Moukhles, A Nieoullon and A Daszuta (1995) Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat.Eur. J. Neurosci. 7, 972–980.PubMedGoogle Scholar
  2. Andersson M, C Konradi and MA Cenci (2001) cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum.J. Neurosci. 21, 9930–9943.PubMedGoogle Scholar
  3. Andrew R, DG Watson, SA Best, JM Midgley, H Wenlong and RK Petty (1993) The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls.Neurochem. Res. 18, 1175–1177.PubMedGoogle Scholar
  4. Anichtchik OV, J Kaslin, N Peitsaro, M Scheinin and P Panula (2004) Neurochemical and behavioural changes in zebrafishDanio rerio after systemic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.J. Neurochem. 88, 443–453.PubMedGoogle Scholar
  5. Arts MP and AR Cools (1998) Bilateral 6-hydroxydopamine lesion in the dopaminergic A8 cell group produces long-lasting deficits in motor programming of cats.Behav. Neurosci. 112, 102–115.PubMedGoogle Scholar
  6. Asanuma M, H Hirata and JL Cadet (1998) Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice.Neuroscience 85, 907–917.PubMedGoogle Scholar
  7. Avila-Costa MR, L Colin-Barenque, P Aley-Medina, AL Valdez, JL Librado, EF Martinez and TI Fortoul (2005) Bilateral increase of perforated synapses after unilateral dopamine depletion.Int. J. Neurosci. 115, 79–86.PubMedGoogle Scholar
  8. Barneoud P, E Descombris, N Aubin and DN Abrous (2000) Evaluation of simple and complex sensorimotor behaviours in rats with a partial lesion of the dopaminergic nigrostriatal system.Eur. J. Neurosci. 12, 322–336.PubMedGoogle Scholar
  9. Barone P, M Morelli, M Popoli, G Cicarelli, G Campanella and G Di Chiara (1994) Behavioural sensitization in 6-hydroxydopamine lesioned rats involves the dopamine signal transduction: changes in DARPP-32 phosphorylation.Neuroscience 61, 867–873.PubMedGoogle Scholar
  10. Bensadoun JC, O Mirochnitchenko, M Inouye, P Aebischer and AD Zurn (1998) Attenuation of 6-OHDA-induced neurotoxicity in glutathione peroxidase transgenic mice.Eur. J. Neurosci. 10, 3231–3236.PubMedGoogle Scholar
  11. Betarbet R, O Poisik, TB Sherer and JT Greenamyre (2004) Differential expression and ser897 phosphorylation of striatalN-methyl-D-aspartate receptor subunit NR1 in animal models of Parkinson’s disease.Exp. Neurol. 187, 76–85.PubMedGoogle Scholar
  12. Blandini F, G Levandis, E Bazzini, G Nappi and MT Armentero (2007) Time-course of nigrostriatal damage, sal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: new clues from an old model.Eur. J. Neurosci. 25, 397–405.PubMedGoogle Scholar
  13. Blum D, S Torch, N Lambeng, M Nissou, AL Benabid, R Sadoul and JM Verna (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, 135–172PubMedGoogle Scholar
  14. Breese GR and TD Traylor (1972) Developmental characteristics of brain catecholamines and tyrosine hydroxylase in the rat: effects of 6-hydroxydopamine.Br. J. Pharmacol. 44, 210–222.PubMedGoogle Scholar
  15. Breese GR, AA Baumeister, TJ McCown, SG Emerick, GD Frye, K Crotty and RA Mueller (1984) Behavioral differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: relevance to neurological symptoms in clinical syndromes with reduced brain dopamine.J. Pharmacol. Exp. Ther. 231, 343–354.PubMedGoogle Scholar
  16. Breese GR, DJ Knapp, HE Criswell, SS Moy, ST Papadeas and BL Blake (2005) The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles.Brain Res. Rev. 48, 57–73.PubMedGoogle Scholar
  17. Cadet JL and C Brannock (1998) Free radicals and the pathobiology of brain dopamine systems.Neurochem. Int. 32, 117–131.PubMedGoogle Scholar
  18. Cadet JL, M Katz, V Jackson-Lewis and S Fahn (1989) Vitamin E attenuates the toxic effects of intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats: behavioral and biochemical evidence.Brain Res. 476, 10–15.PubMedGoogle Scholar
  19. Calabresi P, NB Mercuri, G Sancesario and G Bernardi (1993) Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson’s disease.Brain 116, 433–452.PubMedGoogle Scholar
  20. Callio J, TD Oury and CT Chu (2005) Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains.J. Biol. Chem. 280, 18536–18542.PubMedGoogle Scholar
  21. Caronti B, V Margotta, A Merante, FE Pontieri and G Palladini (1999) Treatment with 6-hydroxydopamine in planaria (Dugesia gonocephala s.l.): morphological and behavioral study.Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol. 123, 201–207.PubMedGoogle Scholar
  22. Carta AR, S Fenu, P Pala, E Tronci and M Morelli (2003) Selective modifications in GAD67 mRNA levels in striatonigral and striatopallidal pathways correlate to dopamine agonist priming in 6-hydroxydopamine-lesioned rats.Eur. J. Neurosci. 18, 2563–2572.PubMedGoogle Scholar
  23. Cass WA, LE Peters and MP Smith (2005) Reductions in spontaneous locomotor activity in aged male, but not female, rats in a model of early Parkinson’s disease.Brain Res. 1034, 153–161.PubMedGoogle Scholar
  24. Cenci MA, CS Lee and A Bjorklund (1998) L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA.Eur. J. Neurosci. 10, 2694–2706.PubMedGoogle Scholar
  25. Chang JW, SR Wachtel, D Young and UJ Kang (1999) Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson’s disease: studies on medial forebrain bundle and striatal lesions.Neuroscience 88, 617–628.PubMedGoogle Scholar
  26. Chase TN and JD Oh (2000) Striatal dopamine- and gluta- mate-mediated dysregulation in experimental parkinsonism.Trends Neurosci. 23, S86-S91.PubMedGoogle Scholar
  27. Choi WS, SY Yoon, TH Oh, EJ Choi, KL O’Malley and YJ Oh (1999) Two distinct mechanisms are involved in 6-hydroxy-dopamine- and MPP+-induced dopaminergic neuronal cell death: role of caspases, ROS, and JNK.J. Neurosci. Res. 57, 86–94.PubMedGoogle Scholar
  28. Cohen G (1984) Oxy-radical toxicity in catecholamine neurons.Neurotoxicology 5, 77–82.PubMedGoogle Scholar
  29. Cohen G, RE Heikkila, B Allis, F Cabt, D Dembiec, D MacNamee, C Mytilineou and B Winston (1976) Destruction of sympathetic nerve terminals by 6-hydroxydopamine: protection by 1-phenyl-3-(2-thiazolyl)-2-thiourea, dieth-yldithiocarmate, methimazole, cysteamine, ethanol and n-butanol.J. Pharmacol. Exp. Ther. 199, 336–352.PubMedGoogle Scholar
  30. Cole RL, C Konradi, J Douglass and SE Hyman (1995) Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum.Neuron 14, 813–823.PubMedGoogle Scholar
  31. Consolo S, M Morelli, M Rimoldi, S Giorgi and G Di Chiara (1999) Increased striatal expression of glutamate decarboxylase 67 after priming of 6-hydroxydopamine-lesioned rats.Neuroscience 89, 1183–1187.PubMedGoogle Scholar
  32. Cousins MS and JD Salamone (1996) Skilled motor deficits in rats induced by ventrolateral striatal dopamine depletions: behavioral and pharmacological characterization.Brain Res. 732,186–194.PubMedGoogle Scholar
  33. Crocker SJ, M Morelli, N Wigle, Y Nakabeppu and GS Robertson (1998) D1- Receptor-related priming is attenuated by antisense-meditated ‘knockdown’ offos-B expression.Mol. Brain Res. 53, 69–77.PubMedGoogle Scholar
  34. Crofts HS, JW Dalley, P Collins, JC Van Denderen, BJ Everitt, TW Robbins and AC Roberts (2001) Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set.Cereb. Cortex 11, 1015–1026.PubMedGoogle Scholar
  35. Cronin-Golomb A, S Corkin and JH Growdon (1994) Impaired problem solving in Parkinson’s disease: impact of a set-shifting deficit.Neuropsychologia 32, 579–593.PubMedGoogle Scholar
  36. D’Hooge R and PP De Deyn (2001) Applications of the Morris water maze in the study of learning and memory.Brain Res. Rev. 36, 60–90.PubMedGoogle Scholar
  37. Dash PK, KA Karl, MA Colicos, R Prywes and ER Kandel (1991) cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase.Proc. Natl. Acad. Sci. USA 88, 5061–5065.PubMedGoogle Scholar
  38. Dauer W and S Przedborski (2003) Parkinson’s disease: mechanisms and models.Neuron 39, 889–909.PubMedGoogle Scholar
  39. Day M, Z Wang, J Ding, X An, CA Ingham, AF Shering, D Wokosin, E Ilijic, Z Sun, AR Sampson, E Mugnaini, AY Deutch, SR Sesack, GW Arbuthnott and DJ Surmeier (2006) Selective elimination of glutamatergic synapses on striato-pallidal neurons in Parkinson disease models.Nat. Neurosci. 9, 251–259.PubMedGoogle Scholar
  40. Deumens R, A Blokland and J Prickaerts (2002) Modeling Parkinson’s disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway.Exp. Neurol. 175, 303–317.PubMedGoogle Scholar
  41. Di Chiara G, M Morelli, P Barone and F Pontieri (1992) Priming as a model of behavioural sensitization.Dev. Pharmacol. Ther. 18, 223–227.PubMedGoogle Scholar
  42. Double KL, M Maywald, M Schmittel, P Riederer and M Gerlach (1998)In vitro studies of ferritin iron release and neurotoxicity.J. Neurochem. 70, 2492–2499.PubMedGoogle Scholar
  43. Dunah AW and DG Standaert (2001) Dopamine D1 receptordependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane.J. Neurosci. 21, 5546–5558.PubMedGoogle Scholar
  44. Dunah AW, Y Wang, RP Yasuda, K Kameyama, RL Huganir, BB Wolfe and DG Standaert (2000) Alterations in subunit expression, composition, and phosphorylation of striatalN-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson’s disease.Mol. Pharmacol. 57, 342–352.PubMedGoogle Scholar
  45. Endepols H, J Schul, HC Gerhardt and W Walkowiak (2004) 6-hydroxydopamine lesions in anuran amphibians: a new model system for Parkinson’s disease?J. Neurobiol. 60, 395–410.PubMedGoogle Scholar
  46. Eslamboli A, HF Baker, RM Ridley and LE Annett (2003) Sensorimotor deficits in a unilateral intrastriatal 6-OHDA partial lesion model of Parkinson’s disease in marmoset monkeys.Exp. Neurol. 183, 418–429.PubMedGoogle Scholar
  47. Ferré S, BB Fredholm, M Morelli, P Popoli and K Fuxe (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the sal ganglia.Trends Neurosci. 20, 482–487.PubMedGoogle Scholar
  48. Finn M, A Jassen, P Baskin and JD Salamone (1997) Tremulous characteristics of the vacuous jaw movements induced by pilocarpine and ventrolateral striatal dopamine depletions.Pharmacol. Biochem. Behav. 57, 243–249.PubMedGoogle Scholar
  49. Franklin L, L Bauce and QJ Pittman (1988) Depletion of central catecholamines reduces pressor responses to arginine vasopressin.Brain Res. 438, 295–298.PubMedGoogle Scholar
  50. Fredduzzi S, R Moratalla, A Monopoli, B Cuellar, K Xu, E Ongini, F Impagnatiello, MA Schwarzschild and JF Chen (2002) Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors.J. Neurosci. 22, 1054–1062.PubMedGoogle Scholar
  51. Freund TF, JF Powell and AD Smith (1984) Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines.Neuroscience 13, 1189–1215.PubMedGoogle Scholar
  52. Ganguly A and KA Keefe (2001) Unilateral dopamine depletion increases expression of the 2A subunit of the N-methyl-D-aspartate receptor in enkephalin-positive and enkephalin-negative neurons.Neuroscience 103, 405–412.PubMedGoogle Scholar
  53. Gardoni F, C Bellone, F Cattabeni and M Di Luca (2001) Protein kinase C activation modulates alpha-calmodulin kinase II binding to NR2A subunit of N-methyl-D-aspartate receptor complex.J. Biol. Chem. 276, 7609–7613.PubMedGoogle Scholar
  54. Garner CD and JP Nachtman (1989) Manganese catalyzed auto-oxidation of dopamine to 6-hydroxydopaminein vitro.Chem. Biol. Interact. 69, 345–351.PubMedGoogle Scholar
  55. Gasrri A, A Sulli, R Innocenzi, C Pacitti and JD Brioni (1996) Spatial memory impairment induced by lesion of the mesohippocampal dopaminergic system in the rat.Neuroscience 74, 1037–1044.Google Scholar
  56. Gerfen CR (2003) D1 dopamine receptor supersensitivity in the dopamine-depleted striatum animal model of Parkinson’s disease.Neuroscientist 9, 455–462.PubMedGoogle Scholar
  57. Gerfen CR, TM Engber, LC Mahan, Z Susel, TN Chase, FJ Monsma Jr and DR Sibley (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and stria-topallidal neurons.Science 250, 1429–1432.PubMedGoogle Scholar
  58. Gerfen CR, S Miyachi, R Paletzki and P Brown (2002) D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase.J. Neurosci. 22, 5042–5054.PubMedGoogle Scholar
  59. Glinka Y and MB Youdim (1995) Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine.Eur. J. Pharmacol. 292, 329–332.PubMedGoogle Scholar
  60. Glinka Y, KF Tipton and MB Youdim (1996) Nature of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine.J. Neurochem. 66, 2004–2010.PubMedGoogle Scholar
  61. Hallett PJ, R Spoelgen, BT Hyman, DG Standaert and AW Dunah (2006) Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking.J. Neurosci. 26, 4690–4700.PubMedGoogle Scholar
  62. Heim C, L Sova, T Kurz, W Kolasiewicz, H Schwegler and KH Sontag (2002) Partial loss of dopaminergic neurons in the substantia nigra, ventrotegmental area and the retrorubral area - model of the early beginning of Parkinson’s symptom- atology?J. Neural Transm. 109, 691–709.PubMedGoogle Scholar
  63. Henderson JM, LE Annett, EM Torres and SB Dunnett (1998) Behavioural effects of subthalamic nucleus lesions in the hemiparkinsonian marmoset(Callithrix jacchus). Eur. J. Neurosci.10, 689–698.PubMedGoogle Scholar
  64. Henry B, AR Crossman and JM Brotchie (1998) Characterization of enhanced behavioral responses to L-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease.Exp. Neurol. 151, 334–342.PubMedGoogle Scholar
  65. Hisatsune C, H Umemori, T Inoue, T Michikawa, K Kohda, K Mikoshi and T Yamamoto (1997) Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin.J. Biol. Chem. 272, 20805–20810.PubMedGoogle Scholar
  66. Hoglinger GU, G Carrard, PP Michel, F Medja, A Lombes, M Ruberg, B Friguet and EC Hirsch (2003) Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease.J. Neurochem. 86, 1297–1307.PubMedGoogle Scholar
  67. Hudson JL, CG van Horne, I Stromberg, S Brock, J Clayton, J Masserano, BJ Hoffer and GA Gerhardt (1993) Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats.Brain Res. 626, 167–174.PubMedGoogle Scholar
  68. Iancu R, P Mohapel, P Brundin and G Paul (2005) Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson’s disease in mice.Behav. Brain Res. 162, 1–10.PubMedGoogle Scholar
  69. Ingham CA, SH Hood, B Van Maldegem, A Weenink and GW Arbuthnott (1993) Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway.Exp. Brain Res. 93, 17–27.PubMedGoogle Scholar
  70. Ingham CA, SH Hood, P Taggart and GW Arbuthnott (1998) Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway.J. Neurosci. 18, 4732–4743.PubMedGoogle Scholar
  71. Jellinger K, L Linert, E Kienzl, E Herlinger and MB Youdim (1995) Chemical evidence for 6-hydroxydopamine to be an endogenous toxic factor in the pathogenesis of Parkinson’s disease.J. Neural Transm. Suppl. 46, 297–314.PubMedGoogle Scholar
  72. Jiang H, V Jackson-Lewis, U Muthane, ADollison, M Ferreira, A Espinosa, B Parsons and S Przedborski (1993) Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats.Brain Res. 613, 347–351.PubMedGoogle Scholar
  73. Jonsson G (1980) Chemical neurotoxins as denervation tools in neurobiology.Annu. Rev. Neurosci. 3, 169–187.PubMedGoogle Scholar
  74. Kayadjanian N, RP Heavens, MJ Besson and DJ Sirinathsinghji (1996) Striatal NMDAR2B mRNA expression after bilateral cortical and unilateral nigral deafferentation.Neuroreport 7, 713–716.PubMedGoogle Scholar
  75. Kelsey JE, SD Mague, RS Pijanowski, RC Harris, NW Kleckner and RT Matthews (2005) NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats.Psychopharmacology 175, 179–188.Google Scholar
  76. Kienzl E, K Jellinger, H Stachelberger and W Linert (1999) Iron as catalyst for oxidative stress in the pathogenesis of Parkinson’s disease?Life Sci. 65, 1973–1976.PubMedGoogle Scholar
  77. Kostrzewa RM, R Brus, JH Kalbfleisch, KW Perry and RW Fuller (1994) Proposed animal model of attention deficit hyperactivity disorder.Brain Res. Bull. 34, 161–167.PubMedGoogle Scholar
  78. Kostrzewa RM, JP Kostrzewa and R Brus (2003) Dopamine receptor supersensitivity: an outcome and index of neurotoxicity.Neurotox. Res. 5, 111–118.PubMedGoogle Scholar
  79. Kostrzewa RM, JP Kostrzewa, R Brus, RA Kostrzewa and P Nowak (2006) Proposed animal model of severe Parkinson’s disease: neonatal 6-hydroxydopamine lesion of dopaminergic innervation of striatum.J. Neural Transm. Suppl. 70, 277–279.PubMedGoogle Scholar
  80. Larson GM, BH Ahlman, CT Bombeck and LM Nyhus (1984) The effect of chemical and surgical sympathectomy on gastric secretion and innervation.Scand. J. Gastroenterol. Suppl. 89, 27–32.PubMedGoogle Scholar
  81. Levin BE and HL Katzen (2005) Early cognitive changes and nondementing behavioral abnormalities in Parkinson’s disease.Adv. Neurol. 96, 84–94.PubMedGoogle Scholar
  82. Liao RM, SC Fowler and MJ Kallman (1997) Quantifying operant behavior deficits in rats with bilateral 6-hydroxydopamine lesions of the ventrolateral striatum.Chin. J. Physiol. 40, 71–78.PubMedGoogle Scholar
  83. Lindner MD, CK Cain, MA Plone, BR Frydel, TJ Blaney, DF Emerich DF and MR Hoane (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, 1–16.PubMedGoogle Scholar
  84. Linert W, E Herlinger, RF Jameson, E Kienzl, K Jellinger and MB Youdim (1996) Dopamine, 6-hydroxydopamine, iron, and dioxygen - their mutual interactions and possible implication in the development of Parkinson’s disease.Biochim. Biophys. Acta 1316, 160–168.PubMedGoogle Scholar
  85. Lotharius J, LL Dugan and KL O’Malley (1999) Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons.J. Neurosci. 19, 1284–1293.PubMedGoogle Scholar
  86. Lundblad M, M Andersson, C Winkler, D Kirik, N Wierup and MA Cenci (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease.Eur. J. Neurosci. 15, 120–132.PubMedGoogle Scholar
  87. Lundblad M, B Picconi, H Lindgren and MA Cenci (2004) A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function.Neurobiol. Dis. 16, 110–123.PubMedGoogle Scholar
  88. Luthman J, A Fredriksson, E Sundstrom, G Jonsson and T Archer (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, 267–277.PubMedGoogle Scholar
  89. Luthman J, M Bassen, A Fredriksson and T Archer (1997) Functional changes induced by neonatal cerebral 6-hydroxy-dopamine treatment: effects of dose levels on behavioral parameters.Behav. Brain Res. 82, 213–221.PubMedGoogle Scholar
  90. Mandel RJ and PK Randall (1985) Quantification of lesion-induced dopaminergic supersensitivity using the rotational model in the mouse.Brain Res. 330, 358–363.PubMedGoogle Scholar
  91. Marin C, E Aguilar, M Bonastre, E Tolosa and JA Obeso (2005) Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats.Exp. Neurol. 192, 184–193.PubMedGoogle Scholar
  92. Marshall JF, R Navarrete and JN Joyce (1989) Decreased striatal D1 binding density following mesotelencephalic 6-hydroxydopamine injections: an autoradiographic analysisBrain Res. 493, 247–257.PubMedGoogle Scholar
  93. Mempel E and M Wieczorek (1990) Parkinson’s syndrome induced in cats by the use of 6-hydroxydopamine. Observations of behavior and motor disorders.Acta Neurobiol. Exp. 50, 269–279.Google Scholar
  94. Menegoz M, LF Lau, D Herve, RL Huganir and JA Girault (1995) Tyrosine phosphorylation of NMD A receptor in rat striatum: effects of 6-OH-dopamine lesions.Neuroreport 7, 125–128.PubMedGoogle Scholar
  95. Meshul CK, N Emre, CM Nakamura, C Allen, MK Donohue and JF Buckman (1999) Time-dependent changes in striatal glutamate synapses following a 6-hydroxydopamine lesion.Neuroscience 88, 1–16.PubMedGoogle Scholar
  96. Mitchell IJ and CB Carroll (1997) Reversal of parkinsonian symptoms in primates by antagonism of excitatory amino acid transmission: potential mechanisms of action.Neurosci. Biobehav. Rev. 21, 469–475.PubMedGoogle Scholar
  97. Montoya CP, LJ Campbell-Hope, KD Pemberton and SB Dunnett (1991) The “staircase test”: a measure of independent forelimb reaching and grasping abilities in rats.J. Neurosci. Meth. 36, 219–228.Google Scholar
  98. Morelli M and G Di Chiara (1987) Agonist-induced homologous and heterologous sensitization to D-1- and D-2-dependent contraversive turning.Eur. J. Pharmacol. 141, 101–107.PubMedGoogle Scholar
  99. Morelli M and G Di Chiara (1990) Stereospecific blockade ofN-methyl-D-aspartate transmission by MK 801 prevents priming of SKF 38393-induced turning.Psychopharmacology 101, 287–288.PubMedGoogle Scholar
  100. Morelli M, S Fenu and G Di Chiara (1987) Behavioural expression of D-1 receptor supersensitivity depends on previous stimulation of D-2 receptors.Life Sci. 40, 245–251.PubMedGoogle Scholar
  101. Morelli M, S Fenu, L Garau and G Di Chiara (1989) Time and dose dependence of the ‘priming’ of the expression of dopamine receptor supersensitivity.Eur. J. Pharmacol. 162, 329–335.PubMedGoogle Scholar
  102. Morelli M, S Fenu, A Pinna, A Cozzolino, A Carta and G Di Chiara (1993a) “Priming” to dopamine agonist-induced contralateral turning as a model of non-associative sensitization to the expression of the post-synaptic dopamine message.Behav. Pharmacol. 4, 389–397.PubMedGoogle Scholar
  103. Morelli M, FE Pontieri, I Linfante, F Orzi and G Di Chiara (1993b) Local cerebral glucose utilization after D1 receptor stimulation in 6-OHDA lesioned rats: effect of sensitization (priming) with a dopaminergic agonist.Synapse 13, 264–269.PubMedGoogle Scholar
  104. Moses D, A Gross and JP Finberg (2004) Rasagiline enhances L-DOPA-induced contralateral turning in the unilateral 6-hydroxydopamine-lesioned guinea-pig.Neuropharmacology 47, 72–80.PubMedGoogle Scholar
  105. Napolitano A, O Crescenzi, A Pezzella and G Prota (1995) Generation of the neurotoxin 6-hydroxydopamine by peroxidase/H2O2 oxidation of dopamine.J. Med. Chem. 38, 917–922.PubMedGoogle Scholar
  106. Nichols AJ, AC Wilson and CR Hiley (1985) Effects of chemical sympathectomy with 6-hydroxydopamine on cardiac output and its distribution in the rat.Eur. J. Pharmacol. 109, 263–268.PubMedGoogle Scholar
  107. Oh JD and TN Chase (2002) Glutamate-mediated striatal dys-regulation and the pathogenesis of motor response complications in Parkinson’s disease.Amino Acids 23, 133–139.PubMedGoogle Scholar
  108. Oh JD, DS Russell, CL Vaughan and TN Chase (1998) Enhanced tyrosine phosphorylation of striatal NMD A receptor subunits: effect of dopaminergic denervation and L-DOPA administration.Brain Res. 813, 150–159.PubMedGoogle Scholar
  109. Oh JD, CL Vaughan and TN Chase (1999) Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal NMDA receptor subunits.Brain Res. 821, 433–442.PubMedGoogle Scholar
  110. Oh JD, K Chartisathian, SM Ahmed and TN Chase (2003) Cyclic AMP responsive element binding protein phosphorylation and persistent expression of levodopa-induced response alterations in unilateral nigrostriatal 6-OHDA lesioned rats.J. Neurosci. Res. 72, 768–780.PubMedGoogle Scholar
  111. Olsson M, G Nikkhah, C Bentlage and A Bjorklund (1995) Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test.J. Neurosci. 15, 3863–3875.PubMedGoogle Scholar
  112. Oueslati A, N Breysse, M Amalric, L Kerkerian-Le Goff and P Salin (2005) Dysfunction of the cortico-sal ganglia-cortical loop in a rat model of early parkinsonism is reversed by metabotropic glutamate receptor 5 antagonism.Eur. J. Neurosci. 22, 2765–2774.PubMedGoogle Scholar
  113. Padiglia A, R Medda, A Lorrai, G Biggio, E Sanna and G Floris (1997) Modulation of 6-hydroxydopamine oxidation by various proteins.Biochem. Pharmacol. 53, 1065–1068.PubMedGoogle Scholar
  114. Palumbo A, A Napolitano, P Barone and M d’Ischia (1999) Nitrite- and peroxide-dependent oxidation pathways of dopamine: 6-nitrodopamine and 6-hydroxydopamine formation as potential contributory mechanisms of oxidative stress- and nitric oxide-induced neurotoxicity in neuronal degeneration.Chem. Res. Toxicol. 12, 1213–1222.PubMedGoogle Scholar
  115. Papa SM, TM Engber, AM Kask and TN Chase (1994) Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration.Brain Res. 662, 69–74.PubMedGoogle Scholar
  116. Papadeas ST, BL Blake, DJ Knapp and GR Breese (2004) Sustained extracellular signal-regulated kinase 1/2 phosphorylation in neonate 6-hydroxydopamine-lesioned rats after repeated D1-dopamine receptor agonist administration: implications for NMDA receptor involvement.J. Neurosci. 24, 5863–5876.PubMedGoogle Scholar
  117. Perumal AS, WK Tordzro, M Katz, V Jackson-Lewis, TB Cooper, S Fahn and JL Cadet (1989) Regional effects of 6-hydroxydopamine (6-OHDA) ton free radical scavengers in rat brain.Brain Res. 504, 139–141.PubMedGoogle Scholar
  118. Picconi B, F Gardoni, D Centonze, D Mauceri, MA Cenci, G Bernardi, P Calabresi and M Di Luca (2004) Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism.J. Neurosci. 24, 5283–5291.PubMedGoogle Scholar
  119. Pileblad E, T Magnusson and B Fornstedt (1989) Reduction of brain glutathione by L-buthionine sulfoximine potentiates the dopamine-depleting action of 6-hydroxydopamine in rat striatum.J. Neurochem. 52, 978–980.PubMedGoogle Scholar
  120. Pilowsky PM, MJ Morris, V Kapoor, MJ West and JP Chalmers (1986) Role of renal nerve activity, plasma catecholamines and plasma vasopressin in cardiovascular responses to intracisternal neurotoxins in the rabbit.J. Auton. Nerv. Syst. 17, 109–120.PubMedGoogle Scholar
  121. Pinna A, M Morelli, B Drukarch and JC Stoof (1997) Priming of 6-hydroxydopamine-lesioned rats with L-DOPA or quinpirole results in an increase in dopamine D1 receptor-dependent cyclic AMP production in striatal tissue.Eur. J. Pharmacol. 331, 23–26.PubMedGoogle Scholar
  122. Pinna A, C Corsi, AR Carta, V Valentini, F Pedata and M Morelli (2002) Modification of adenosine extracellular levels and adenosine A(2A) receptor mRNA by dopamine denervation.Eur. J. Pharmacol. 446, 75–82.PubMedGoogle Scholar
  123. Ramesh V and V Mohan-Kumar (2000) Changes in sleep-wakefulness after 6-hydroxydopamine lesion of the preoptic area.Neuroscience 98, 549–553.PubMedGoogle Scholar
  124. Ridet JL, JC Bensadoun, N Deglon, P Aebischer and AD Zurn (2006) Lentivirus-mediated expression of glutathione per-oxidase: neuroprotection in murine models of Parkinson’s disease.Neurobiol. Dis. 21, 29–34.PubMedGoogle Scholar
  125. Ridley RM, RM Cummings, A Leow-Dyke and HF Baker (2006) Neglect of memory after dopaminergic lesions in monkeys.Behav. Brain Res. 166, 253–262.PubMedGoogle Scholar
  126. Salamone JD, K Mahan and S Rogers (1993) Ventrolateral striatal dopamine depletions impair feeding and food handling in rats.Pharmacol. Biochem. Behav. 44, 605–610.PubMedGoogle Scholar
  127. Salamone JD, AJ Mayorga, JT Trevitt, MS Cousins, A Conlan and A Nawab (1998) Tremulous jaw movements in rats: a model of parkinsonian tremor.Prog. Neurobiol. 56, 591–611.PubMedGoogle Scholar
  128. Samuel D, M Errami and A Nieoullon (1990) Localization ofN-methyl-D-aspartate receptors in the rat striatum: effects of specific lesions on the [3H3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid binding.J. Neurochem. 54, 1926–1933.PubMedGoogle Scholar
  129. Schallert T, SM Fleming, JL Leasure, JL Tillerson and ST Bland (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury.Neuropharmacology 39, 777–787.PubMedGoogle Scholar
  130. Schiffmann SN, O Jacobs and JJ Vanderhaeghen (1991) Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: anin situ hybridization histochemistry study.J. Neurochem. 57, 1062–1067.PubMedGoogle Scholar
  131. Schwarzkopf SB, JP Bruno, T Mitra and JR Ison (1996) Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes.Psychopharmacology 123, 258–266.PubMedGoogle Scholar
  132. Sgamto V, C Pages, M Rogard, MJ Besson, J Caboche (1998) Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostriatal stimulation.J. Neurosci. 18, 8814–8825.Google Scholar
  133. Sheng M, MA Thompson and ME Greenberg (1991) CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases.Science 252, 1427–1430.PubMedGoogle Scholar
  134. Somogyi P, JP Bolam, S Totterdell and AD Smith (1981) Monosynaptic input from the nucleus accumbens — ventral striatum region to retrogradely labelled nigrostriatal neurones.Brain Res. 217, 245–263.PubMedGoogle Scholar
  135. Soto-Otero R, E Mendez-Alvarez, A Hermida-Ameijeiras, AM Munoz-Patino and JL Landeira-Garcia (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease.J. Neurochem. 74, 1605–1612.PubMedGoogle Scholar
  136. Storch A, A Kaftan, K Burkhardt and J Schwarz (2000) 6-Hydroxydopamine toxicity towards human SH-SY5Y dopaminergic neuroblastoma cells: independent of mitochondrial energy metabolism.J. Neural Transm. 107, 281–293.PubMedGoogle Scholar
  137. Sudo A (1985) Decrease in adrenaline content of various organs of the rat after 6-hydroxydopamine.Eur. J. Pharmacol. 114, 79–83.PubMedGoogle Scholar
  138. Sunn N, PJ Harris and C Bell (1990) Effects on renal sympathetic axons in dog of acute 6-hydroxydopamine treatment in combination with selective neuronal uptake inhibitors.Br. J. Pharmacol. 99, 655–660.PubMedGoogle Scholar
  139. Takasuna M and T Iwasaki (1996) Active and passive avoidance learning in rats neonatally treated with intraventricular 6-hydroxydopamine.Behav. Brain Res. 74, 119–126.PubMedGoogle Scholar
  140. Thoenen H (1972) Surgical, immunological and chemical sympathectomy, In:Handbook of Experimental Pharmacology (Blaschko H and E Muscholl, Eds.) (Springer:Berlin)33, 813–844.Google Scholar
  141. Turle-Lorenzo N, N Breysse, G Baunez and M Amalric (2005) Functional interaction between mGlu 5 and NMDA receptors in a rat model of Parkinson’s disease.Psychopharmacology 179, 117–127.PubMedGoogle Scholar
  142. Ulas J and CW Cotman (1996) Dopaminergic denervation of striatum results in elevated expression of NR2A subunit.Neuroreport 7, 1789–1793.PubMedGoogle Scholar
  143. Ungerstedt U and G Arbuthnott (1970) Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system.Brain Res. 24, 485–493.PubMedGoogle Scholar
  144. Vallone D, MT Pellecchia, M Morelli, P Verde, G DiChiara and P Barone (1997) Behavioural sensitization in 6-hydroxydo- pamine-lesioned rats is related to compositional changes of the AP-1 transcription factor: evidence for induction offos-B- andjun-D-related proteins.Mol. Brain Res. 52, 307–317.PubMedGoogle Scholar
  145. Van de Witte SV, B Drukarch, JC Stoof and P Voorn (1998) Priming with L-DOPA differently affects dynorphin and substance P mRNA levels in the striatum of 6-hydroxydopa-mine-lesioned rats after challenge with dopamine D1-receptor agonist.Mol. Brain Res. 61, 219–223.PubMedGoogle Scholar
  146. Van Kampen JM, EG McGeer and AJ Stoessl (2000) Dopamine transporter function assessed by antisense knockdown in the rat: protection from dopamine neurotoxicity.Synapse 37, 171–178.PubMedGoogle Scholar
  147. Villanueva MM, P Soares-da-Silva and W Osswald (1994) Effect of sympathetic denervation on the relaxing responses of rabbit arterial smooth muscle.J. Auton. Pharmacol. 14, 275–281.PubMedGoogle Scholar
  148. Wang YT and MW Salter (1994) Regulation of NMDA receptors by tyrosine kinases and phosphatases.Nature 369, 233–235.PubMedGoogle Scholar
  149. Whishaw IQ, NC Woodward, E Miklyaeva and SM Pellis (1997) Analysis of limb use by control rats and unilateral DA-depleted rats in the Montoya staircase test: movements, impairments and compensatory strategies.Behav. Brain Res. 89, 167–177.PubMedGoogle Scholar
  150. Woodlee MT, AM Asseo-Garcia, X Zhao, SJ Liu, TA Jones and T Schallert (2005) Testing forelimb placing “across the midline” reveals distinct, lesion-dependent patterns of recovery in rats.Exp. Neurol. 191, 310–317.PubMedGoogle Scholar
  151. Wu Y, D Blum, MF Nissou, AL Benabid and JM Verna (1996) Unlike MPP+, apoptosis induced by 6-OHDA in PC12 cells is independent of mitochondrial inhibition.Neurosci. Lett. 221, 69–71.PubMedGoogle Scholar
  152. Yanai J,WF Silverman and D Shamir (1995) An avian model for the reversal of 6-hydroxydopamine induced rotating behaviour by neural grafting.Neurosci. Lett. 187, 153–156.PubMedGoogle Scholar
  153. Youdim MB, G Stephenson and D Ben Shachar (2004) Ironing iron out in Parkinson’s disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28.Ann. NYAcad. Sci. 1012, 306–325.Google Scholar
  154. Zrsky V, KP Datla, S Parkar, DK Rai, OI Aruoma and DT Dexter (2005) Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease.Free Radic. Res. 39, 1119–1125.Google Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Nicola Simola
    • 1
  • Micaela Morelli
    • 2
  • Anna R. Carta
    • 1
  1. 1.Department of ToxicologyUniversity of CagliariCagliariItaly
  2. 2.CNR Institute for Neuroscience — Section of CagliaryItaly

Personalised recommendations