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Journal of Neural Transmission

, Volume 125, Issue 8, pp 1137–1144 | Cite as

Animal models of l-DOPA-induced dyskinesia: the 6-OHDA-lesioned rat and mouse

  • Elisabetta TronciEmail author
  • Veronica Francardo
Neurology and Preclinical Neurological Studies - Review Article

Abstract

Appearance of l-DOPA-induced dyskinesia (LID) represents a major limitation in the pharmacological therapy with the dopamine precursor l-DOPA. Indeed, the vast majority of parkinsonian patients develop dyskinesia within 9–10 years of l-DOPA oral administration. This makes the discovery of new therapeutic strategies an important need. In the last decades, several animal models of Parkinson’s disease (PD) have been developed, to both study mechanisms underlying PD pathology and treatment-induced side effects (i.e., LID) and to screen for new potential anti-parkinsonian and anti-dyskinetic treatments. Among all the models developed, the 6-OHDA-lesioned rodents represent the models of choice to mimic PD motor symptoms and LID, thanks to their reproducibility and translational value. Under l-DOPA treatment, rodents sustaining 6-OHDA lesions develop abnormal involuntary movements with dystonic and hyperkinetic features, resembling what seen in dyskinetic PD patients. These models have been extensively validated by the evidence that dyskinetic behaviors are alleviated by compounds reducing dyskinesia in patients and non-human primate models of PD. This article will focus on the translational value of the 6-OHDA rodent models of LID, highlighting their main features, advantages and disadvantages in preclinical research.

Keywords

Parkinson’s disease l-DOPA Dyskinesia 6-OHDA Rodent model 

Notes

Acknowledgements

Veronica Francardo is supported by grants from the Swedish Parkinson Foundation, The Greta and Johan Kocks Foundation, and the Michael J Fox Foundation.

References

  1. Alcacer C, Andreoli L, Sebastianutto I et al (2017) Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy. J Clin Investig 127:720–734CrossRefPubMedGoogle Scholar
  2. Amalric M, Moukhles H, Nieoullon A, Daszuta A (1995) Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat. Eur J Neurosci 7:972–980CrossRefPubMedGoogle Scholar
  3. Andersson M, Hilbertson A, Cenci MA (1999) Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease. Neurobiol Dis 6:461–474CrossRefPubMedGoogle Scholar
  4. Antonini A, Ursino G, Calandrella D et al (2010) Continuous dopaminergic delivery in Parkinson’s disease. J Neurol 257:S305–S308CrossRefPubMedGoogle Scholar
  5. Bastide MF, Meissner WG, Picconi B et al (2015) Pathophysiology of l-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol 132:96–168CrossRefPubMedGoogle Scholar
  6. Berton O, Guigoni C, Li Q et al (2009) Striatal overexpression of DeltaJunD resets l-DOPA-induced dyskinesia in a primate model of Parkinson disease. Biol Psychiatry 66:554–561CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bez F, Francardo V, Cenci MA (2016) Dramatic differences in susceptibility to l-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion. Neurobiol Dis 94:213–225CrossRefPubMedGoogle Scholar
  8. Bezard E, Tronci E, Pioli EY et al (2013) Study of the antidyskinetic effect of eltoprazine in animal models of levodopa-induced dyskinesia. Mov Disord 28:1088–1096CrossRefPubMedGoogle Scholar
  9. Blesa J, Phani S, Jackson-Lewis V, Przedborski S (2012) Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol 2012:845618CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bracco F, Battaglia A, Chouza C et al (2004) The long-acting dopamine receptor agonist cabergoline in early Parkinson’s disease: final results of a 5-year, double-blind, levodopa-controlled study. CNS Drugs 18:733–746CrossRefPubMedGoogle Scholar
  11. Cao X, Yasuda T, Uthayathas S et al (2010) Striatal overexpression of DeltaFosB reproduces chronic levodopa-induced involuntary movements. J Neurosci 30:7335–7343CrossRefPubMedPubMedCentralGoogle Scholar
  12. Carlsson A, Lindqvist M, Magnusson T (1957) 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180:1200CrossRefPubMedGoogle Scholar
  13. Carta M, Tronci E (2014) Serotonin system implication in l-DOPA-induced dyskinesia: from animal models to clinical investigations. Front Neurol 5:78CrossRefPubMedPubMedCentralGoogle Scholar
  14. Carta M, Carlsson T, Kirik D et al (2007) Dopamine released from 5-HT terminals is the cause of l-DOPA-induced dyskinesia in parkinsonian rats. Brain 130:1819–1833CrossRefPubMedGoogle Scholar
  15. Carta M, Carlsson T, Muñoz A et al (2008) Involvement of the serotonin system in l-dopa-induced dyskinesias. Parkinsonism Relat Disord 14(Suppl 2):S154–S158CrossRefPubMedGoogle Scholar
  16. Carta M, Carlsson T, Muñoz A et al (2010) Role of serotonin neurons in the induction of levodopa- and graft-induced dyskinesias in Parkinson’s disease. Mov Disord 25:S174–S179CrossRefPubMedGoogle Scholar
  17. Cenci MA, Konradi C (2010) Maladaptive striatal plasticity in l-DOPA-induced dyskinesia. Prog Brain Res 183:209–233CrossRefPubMedPubMedCentralGoogle Scholar
  18. Cenci MA, Lee CS, Björklund A (1998) l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur J Neurosci 10:2694–2706CrossRefPubMedGoogle Scholar
  19. Cenci MA, Ohlin KE, Rylander D (2009) Plastic effects of l-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia. Parkinsonism Relat Disord 15(Suppl 3):S59–S63CrossRefPubMedGoogle Scholar
  20. Cicchetti F, Brownell AL, Williams K et al (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15:991–998CrossRefPubMedGoogle Scholar
  21. Cohen G (1984) Oxy-radical toxicity in catecholamine neurons. Neurotoxicology 5:77–82PubMedGoogle Scholar
  22. Date I, Felten DL, Felten SY (1990) Long-term effect of MPTP in the mouse brain in relation to aging: neurochemical and immunocytochemical analysis. Brain Res 519:266–276CrossRefPubMedGoogle Scholar
  23. de la Fuente-Fernández R, Sossi V, Huang Z et al (2004) Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias. Brain 127:2747–2754CrossRefPubMedGoogle Scholar
  24. De Leonibus E, Pascucci T, Lopez S et al (2007) Spatial deficits in a mouse model of Parkinson disease. Psychopharmacology 194:517–525CrossRefPubMedGoogle Scholar
  25. Decressac M, Mattsson B, Björklund A (2012) Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson’s disease. Exp Neurol 235:306–315CrossRefPubMedGoogle Scholar
  26. Dekundy A, Lundblad M, Danysz W, Cenci MA (2007) Modulation of l-DOPA-induced abnormal involuntary movements by clinically tested compounds: further validation of the rat dyskinesia model. Behav Brain Res 179:76–89CrossRefPubMedGoogle Scholar
  27. Delfino M, Stefano A, Ferrario J et al (2004) Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias. Behav Brain Res 152:297–306CrossRefPubMedGoogle Scholar
  28. Ding Y, Restrepo J, Won L et al (2007) Chronic 3,4-dihydroxyphenylalanine treatment induces dyskinesia in aphakia mice, a novel genetic model of Parkinson’s disease. Neurobiol Dis 27:11–23CrossRefPubMedPubMedCentralGoogle Scholar
  29. Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164:1357–1391CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fahn S (2003) Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14CrossRefPubMedGoogle Scholar
  31. Fahn S (2015) The medical treatment of Parkinson disease from James Parkinson to George Cotzias. Mov Disord 30:4–18CrossRefPubMedGoogle Scholar
  32. Fasano S, Bezard E, D’Antoni A et al (2010) Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with l-dopa-induced dyskinesia. Proc Natl Acad Sci USA 107:21824–21829CrossRefPubMedGoogle Scholar
  33. Francardo V, Cenci MA (2014) Investigating the molecular mechanisms of l-DOPA-induced dyskinesia in the mouse. Parkinsonism Relat Disord 20(Suppl 1):S20–S22CrossRefPubMedGoogle Scholar
  34. Francardo V, Recchia A, Popovic N et al (2011) Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to l-DOPA in the 6-hydroxydopamine mouse model of Parkinson’s disease. Neurobiol Dis 42:327–340CrossRefPubMedGoogle Scholar
  35. Ghiglieri V, Mineo D, Vannelli A et al (2016) Modulation of serotonergic transmission by eltoprazine in l-DOPA-induced dyskinesia: behavioral, molecular, and synaptic mechanisms. Neurobiol Dis 86:140–153CrossRefPubMedGoogle Scholar
  36. Henry B, Crossman AR, Brotchie JM (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 151:334–342CrossRefPubMedGoogle Scholar
  37. Hernández LF, Castela I, Ruiz-DeDiego I et al (2017) Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease. Mov Disord 32:530–537CrossRefGoogle Scholar
  38. Holloway RG, Shoulson I, Fahn S et al (2004) Pramipexole vs levodopa as initial treatment for Parkinson disease. Arch Neurol 61:1044–1053PubMedGoogle Scholar
  39. Hope BT, Nye HE, Kelz MB et al (1994) Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13:1235–1244CrossRefPubMedGoogle Scholar
  40. Iderberg H, Francardo V, Pioli EY (2012) Animal models of l-DOPA-induced dyskinesia: an update on the current options. Neurosci 211:13–27CrossRefPubMedGoogle Scholar
  41. Iderberg H, McCreary AC, Varney MA et al (2015) Activity of serotonin 5-HT(1A) receptor “biased agonists” in rat models of Parkinson’s disease and l-DOPA-induced dyskinesia. Neuropharmacology 93:52–67CrossRefPubMedGoogle Scholar
  42. Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2:141–151CrossRefPubMedGoogle Scholar
  43. Jankovic J, Stacy M (2007) Medical management of levodopa-associated motor complications in patients with Parkinson’s disease. CNS Drugs 21:677–692CrossRefPubMedGoogle Scholar
  44. Kirik D, Rosenblad C, Björklund A (1998) Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152:259–277CrossRefPubMedGoogle Scholar
  45. Lindgren HS, Rylander D, Ohlin KE et al (2007) The “motor complication syndrome” in rats with 6-OHDA lesions treated chronically with l-DOPA: relation to dose and route of administration. Behav Brain Res 177:150–159CrossRefPubMedGoogle Scholar
  46. Lindgren HS, Andersson DR, Lagerkvist S et al (2010) l-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson’s disease: temporal and quantitative relationship to the expression of dyskinesia. J Neurochem 112:1465–1476CrossRefPubMedGoogle Scholar
  47. Lundblad M, Andersson M, Winkler C et al (2002) Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci 15:120–132CrossRefPubMedGoogle Scholar
  48. Lundblad M, Picconi B, Lindgren H, Cenci MA (2004) A model of l-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 16:110–123CrossRefPubMedGoogle Scholar
  49. Lundblad M, Usiello A, Carta M et al (2005) Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia. Exp Neurol 194:66–75CrossRefPubMedGoogle Scholar
  50. Manson A, Stirpe P, Schrag A (2012) Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Parkinsons Dis 2:189–198PubMedGoogle Scholar
  51. Mazzio EA, Reams RR, Soliman KFA (2004) The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro. Brain Res 1004:29–44CrossRefPubMedGoogle Scholar
  52. Mela F, Marti M, Bido S et al (2012) In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels. Neurobiol Dis 45:573–582CrossRefPubMedGoogle Scholar
  53. Mitsumoto Y, Watanabe A, Mori A, Koga N (1998) Spontaneous regeneration of nigrostriatal dopaminergic neurons in MPTP-treated C57BL/6 mice. Biochem Biophys Res Commun 248:660–663CrossRefPubMedGoogle Scholar
  54. Mulas G, Espa E, Fenu S et al (2016) Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson’s disease. Exp Neurol 286:83–92CrossRefPubMedGoogle Scholar
  55. Nadjar A, Gerfen CR, Bezard E (2009) Priming for l-dopa-induced dyskinesia in Parkinson’s disease: a feature inherent to the treatment or the disease? Prog Neurobiol 87:1–9CrossRefPubMedGoogle Scholar
  56. Nicholas AP (2007) Levodopa-induced hyperactivity in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Mov Disord 22:99–104CrossRefPubMedGoogle Scholar
  57. Olanow CW, Agid Y, Mizuno Y et al (2004) Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 19:997–1005CrossRefPubMedGoogle Scholar
  58. Olsson M, Nikkhah G, Bentlage C, Björklund A (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 15:3863–3875CrossRefPubMedGoogle Scholar
  59. Paillé V, Henry V, Lescaudron L et al (2007) Rat model of Parkinson’s disease with bilateral motor abnormalities, reversible with levodopa, and dyskinesias. Mov Disord 22:533–539CrossRefPubMedGoogle Scholar
  60. Papa SM, Engber TM, Kask AM, Chase TN (1994) Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 662:69–74CrossRefPubMedGoogle Scholar
  61. Papathanou M, Rose S, McCreary A, Jenner P (2011) Induction and expression of abnormal involuntary movements is related to the duration of dopaminergic stimulation in 6-OHDA-lesioned rats. Eur J Neurosci 33:2247–2254CrossRefPubMedGoogle Scholar
  62. Paquette MA, Martinez AA, Macheda T et al (2012) Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson’s disease: role of NMDA vs. 5-HT1A receptors. Eur J Neurosci 36:3224–3234CrossRefPubMedPubMedCentralGoogle Scholar
  63. Pavón N, Martín AB, Mendialdua A, Moratalla R (2006) ERK phosphorylation and FosB expression are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry 59:64–74CrossRefPubMedGoogle Scholar
  64. Perfeito R, Cunha-Oliveira T, Rego AC (2013) Reprint of: revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse. Free Radic Biol Med 62:186–201CrossRefPubMedGoogle Scholar
  65. Picconi B, Paillé V, Ghiglieri V et al (2008) l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation. Neurobiol Dis 29:327–335CrossRefPubMedGoogle Scholar
  66. Pinna A, Morelli M (2014) A critical evaluation of behavioral rodent models of motor impairment used for screening of antiparkinsonian activity: the case of adenosine A2A receptor antagonists. Neurotox Res 25:392–401CrossRefPubMedGoogle Scholar
  67. Pinna A, Ko WK, Costa G et al (2015) Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson’s disease. Mov Disord 31:501–511CrossRefGoogle Scholar
  68. Politis M, Wu K, Loane C et al (2014) Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Investig 124:1340–1349CrossRefPubMedGoogle Scholar
  69. Przedborski S, Levivier M, Jiang H et al (1995) Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67:631–647CrossRefPubMedGoogle Scholar
  70. Putterman DB, Munhall AC, Kozell LB et al (2007) Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopa-induced dyskinesia in a rat model of Parkinson’s disease. J Pharmacol Exp Ther 323:277–284CrossRefPubMedGoogle Scholar
  71. Rascol O, Brooks DJ, Korczyn AD et al (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med 342:1484–1491CrossRefPubMedGoogle Scholar
  72. Sahin G, Thompson LH, Lavisse S et al (2014) Differential dopamine receptor occupancy underlies l-DOPA-induced dyskinesia in a rat model of parkinson’s disease. PLoS One 9:e90759CrossRefPubMedPubMedCentralGoogle Scholar
  73. Sakai K, Gash DM (1994) Effect of bilateral 6-OHDA lesions of the substantia nigra on locomotor activity in the rat. Brain Res 633:144–150CrossRefPubMedGoogle Scholar
  74. Santini E, Valjent E, Usiello A et al (2007) Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in l-DOPA-induced dyskinesia. J Neurosci 27:6995–7005CrossRefPubMedGoogle Scholar
  75. Sawada H, Oeda T, Kuno S et al (2010) Amantadine for dyskinesias in Parkinson’s disease: a randomized controlled trial. PLoS One 5:e15298CrossRefPubMedPubMedCentralGoogle Scholar
  76. 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
  77. Sebastianutto I, Maslava N, Hopkins CR, Cenci MA (2016) Validation of an improved scale for rating l-DOPA-induced dyskinesia in the mouse and effects of specific dopamine receptor antagonists. Neurobiol Dis 96:156–170CrossRefPubMedGoogle Scholar
  78. Sedelis M, Hofele K, Auburger GW et al (2000) MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet 30:171–182CrossRefPubMedGoogle Scholar
  79. Stocchi F, Vacca L, Ruggieri S, Olanow CW (2005) Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 62:905–910CrossRefPubMedGoogle Scholar
  80. Tanaka H, Kannari K, Maeda T et al (1999) Role of serotonergic neurons in l-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. NeuroReport 10:631–634CrossRefPubMedGoogle Scholar
  81. Taylor JL, Bishop C, Walker PD (2005) Dopamine D1 and D2 receptor contributions to l-DOPA-induced dyskinesia in the dopamine-depleted rat. Pharmacol Biochem Behav 81:887–893CrossRefPubMedGoogle Scholar
  82. Tronci E, Shin E, Björklund A, Carta M (2012) Amphetamine-induced rotation and l-DOPA-induced dyskinesia in the rat 6-OHDA model: a correlation study. Neurosci Res 73:168–172CrossRefPubMedGoogle Scholar
  83. Tronci E, Lisci C, Stancampiano R et al (2013) 5-Hydroxy-tryptophan for the treatment of l-DOPA-induced dyskinesia in the rat Parkinson’s disease model. Neurobiol Dis 60:108–114CrossRefPubMedGoogle Scholar
  84. Tronci E, Fidalgo C, Carta M (2014) The serotonergic system in l-DOPA-induced dyskinesia. In: Fox S, Brotchie J (eds) Levodopa-Induced Dyskinesia in Parkinson's Disease. Springer, London, pp 199–212Google Scholar
  85. Tronci E, Fidalgo C, Stancampiano R, Carta M (2015) Effect of selective and non-selective serotonin receptor activation on l-DOPA-induced therapeutic efficacy and dyskinesia in parkinsonian rats. Behav Brain Res 292:300–304CrossRefPubMedGoogle Scholar
  86. Ulusoy A, Sahin G, Kirik D (2010) Presynaptic dopaminergic compartment determines the susceptibility to l-DOPA-induced dyskinesia in rats. Proc Natl Acad Sci 107:13159–13164CrossRefPubMedGoogle Scholar
  87. Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110CrossRefPubMedGoogle Scholar
  88. Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93CrossRefPubMedGoogle Scholar
  89. Westin JE, Vercammen L, Strome EM et al (2007) Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of l-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 62:800–810CrossRefPubMedPubMedCentralGoogle Scholar
  90. Winkler C, Kirik D, Björklund A, Dunnett SB (2000) Transplantation in the rat model of Parkinson’s disease: ectopic versus homotopic graft placement. Prog Brain Res 127:233–265CrossRefPubMedGoogle Scholar
  91. Winkler C, Kirik D, Björklund A, Cenci MA (2002) L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of Parkinson’s disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 10:165–186CrossRefPubMedGoogle Scholar
  92. Zhang Z, Andersen A, Smith C et al (2010) Motor slowing and parkinsonian signs in aging rhesus monkeys mirror human aging. J Gerontol A Biol Sci Med Sci 55:B473–B480CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Biomedical Sciences, Section of PhysiologyUniversity of CagliariMonserratoItaly
  2. 2.Basal Ganglia Pathophysiology Unit, Department of Experimental Medical ScienceLund UniversityLundSweden

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