Cellular and Molecular Life Sciences

, Volume 72, Issue 11, pp 2107–2117 | Cite as

Molecular imaging of levodopa-induced dyskinesias

  • Flavia Niccolini
  • Lorenzo Rocchi
  • Marios Politis


Levodopa-induced dyskinesias (LIDs) occur in the majority of patients with Parkinson’s disease (PD) following years of levodopa treatment. The pathophysiology underlying LIDs in PD is poorly understood, and current treatments generate only minor benefits for the patients. Studies with positron emission tomography (PET) molecular imaging have demonstrated that in advanced PD patients, levodopa administration induces sharp increases in striatal dopamine levels, which correlate with LIDs severity. Fluctuations in striatal dopamine levels could be the result of the attenuated buffering ability in the dopaminergically denervated striatum. Lines of evidence from PET studies indicate that serotonergic terminals could also be responsible for the development of LIDs in PD by aberrantly processing exogenous levodopa and by releasing dopamine in a dysregulated manner from the serotonergic terminals. Additionally, other downstream mechanisms involving glutamatergic, cannabinoid, opioid, cholinergic, adenosinergic, and noradrenergic systems may contribute in the development of LIDs. In this article, we review the findings from preclinical, clinical, and molecular imaging studies, which have contributed to our understanding the pathophysiology of LIDs in PD.


Dyskinesias Graft-induced dyskinesias Levodopa-induced dyskinesias Parkinson’s disease PET 



Graft-induced dyskinesias


Levodopa-induced dyskinesias


Positron emission tomography


Parkinson’s disease



Flavia Niccolini research was supported from Parkinson’s UK. Lorenzo Rocchi research is supported from the Lily and Edmond J. Safra Foundation. Marios Politis research was supported by Parkinson’s UK, Lily and Edmond J. Safra Foundation, Imanova ltd, Michael J Fox Foundation (MJFF), and NIHR BRC.

Conflict of interest

The authors declare no financial or other conflict of interest.


  1. 1.
    MacDonald BK, Cockerell OC, Sander WAS, Shorvon SD (2000) The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 123:665–676PubMedGoogle Scholar
  2. 2.
    Ahlskog JE, Muenter MD (2001) Frequency of levodopa-related dyskinesisa and motor fluctuations as estimated from the cumulative literature. Mov Disord 16:448–458PubMedGoogle Scholar
  3. 3.
    Olanow CW, Obeso JA, Stocchi F (2006) Continuous dopaminergic stimulation in the treatment of Parkinson’s disease. Nat Clin Pract Neurol 2:382–392PubMedGoogle Scholar
  4. 4.
    Nutt JG, Chung KA, Holford NH (2010) Dyskinesia and the antiparkinsonian response always temporally coincide: a retrospective study. Neurology 74:1191–1197PubMedCentralPubMedGoogle Scholar
  5. 5.
    Jankovic J (2005) Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord 20(Suppl 11):S11–S16PubMedGoogle Scholar
  6. 6.
    Fabbrini G, Brotchie JM, Grandas F, Nomoto M, Goetz CG (2007) Levodopa-induced dyskinesias. Mov Disord 22:1379–1389PubMedGoogle Scholar
  7. 7.
    Fahn S (2008) How do you treat motor complications in Parkinson’s disease: medicine, surgery, or both? Ann Neurol 64(Suppl 2):S56–S64PubMedGoogle Scholar
  8. 8.
    Khlebtovsky A, Rigbi A, Melamed E, Ziv I, Steiner I, Gad A, Djaldetti R (2012) Patient and caregiver perceptions of the social impact of advanced Parkinson’s disease and dyskinesias. J Neural Transm 119:1367–1371PubMedGoogle Scholar
  9. 9.
    Suh DC, Pahwa R, Mallya U (2012) Treatment patterns and associated costs with Parkinson’s disease levodopa induced dyskinesia. J Neurol Sci 319(1–2):24–31PubMedGoogle Scholar
  10. 10.
    Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B (2010) Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol 9:1106–1117PubMedGoogle Scholar
  11. 11.
    Meissner W, Ravenscroft P, Reese R, Harnack D, Morgenstern R, Kupsch A, Klitgaard H, Bioulac B, Gross CE, Bezard E, Boraud T (2006) Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracellular striatal dopamine. Neurobiol Dis 22:586–598PubMedGoogle Scholar
  12. 12.
    Lindgren HS, Andersson DR, Lagerkvist S, Nissbrandt H, Cenci MA (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 112:1456–1476Google Scholar
  13. 13.
    Ng KY, Colburn RW, Kopin IJ (1971) Effects of l-dopa on efflux of cerebral monoamines from synaptosomes. Nature 230:331–332PubMedGoogle Scholar
  14. 14.
    Arai R, Karasawa N, Geffard M, Nagatsu I (1995) l-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a doublelabeling immunofluorescence study. Neurosci Lett 195:195–198PubMedGoogle Scholar
  15. 15.
    Arai R, Karasawa N, Geffard M, Nagatsu T, Nagatsu I (1994) Immunohistochemical evidence that central serotonin neurons produce dopamine from exogenous l-DOPA in the rat, with reference to the involvement of aromatic l-amino acid decarboxylase. Brain Res 667:295–299PubMedGoogle Scholar
  16. 16.
    Tanaka H, Kannari K, Maeda T, Tomiyama M, Suda T, Matsunaga M (1999) Role of serotonergic neurons in l-DOPA derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. NeuroReport 10:631–634PubMedGoogle Scholar
  17. 17.
    Maeda T, Nagata K, Yoshida Y, Kannari K (2005) Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA. Brain Res 1046:230–233PubMedGoogle Scholar
  18. 18.
    Carta M, Carlsson T, Kirik D, Björklund A (2007) Dopamine released from 5-HT terminals is the cause of l-DOPA-induced dyskinesia in parkinsonian rats. Brain 130:1819–1833PubMedGoogle Scholar
  19. 19.
    Bibbiani F, Oh JD, Chase TN (2001) Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 57:18–29Google Scholar
  20. 20.
    Eskow KL, Gupta V, Alam S, Park JY, Bishop C (2007) The partial 5-HT1A agonist buspirone reduces the expression and development of l-DOPA-induced dyskinesia in rats and improvesl-DOPA efficacy. Pharmacol Biochem Behav 87:306–314PubMedGoogle Scholar
  21. 21.
    Muñoz A, Qin L, Gardoni F, Marcello E, Qin C, Carlsson T, Kirik D, Di Luca M, Björklund A, Bezard E, Carta M (2008) Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia. Brain 131:3380–3394PubMedGoogle Scholar
  22. 22.
    Muñoz A, Carlsson T, Tronci E, Kirik, Björklund A, Carta M (2009) Serotonin neuron-dependent and -independent reduction of dyskinesia by 5-HT1A and 5-HT1B receptor agonists in the rat Parkinson model. Exper Neurol 219:298–307Google Scholar
  23. 23.
    Bishop C, Krolewski D, Eskow K, Barnum C, Dupre K, Deak T, Walker P (2009) Contribution of the striatum to the effects of 5-HT1A receptor stimulation in l-DOPA-treated hemiparkinsonian rats. J Neurosci Res 87:1645–1658PubMedCentralPubMedGoogle Scholar
  24. 24.
    Grégoire L, Samadi P, Grahama J, Bedard P, Bartoszyk G, Di Paolo T (2009) Low doses of sarizotan reduce dyskinesias and maintain antiparkinsonian efficacy of l-Dopa in parkinsonian monkeys. Parkins Rel Disord 15:445–452Google Scholar
  25. 25.
    Loane C, Politis M (2012) Buspirone: what is it all about? Brain Res 1461:111–118PubMedGoogle Scholar
  26. 26.
    Bézard E, Muñoz A, Tronci E, Pioli EY, Li Q, Porras G, Björklund A, Carta M (2013) Anti-dyskinetic effect of anpirtoline in animal models of l-DOPA-induced dyskinesia. Neurosci Res 77(4):242–246PubMedGoogle Scholar
  27. 27.
    Mignon LJ, Wolf WA (2005) 8-Hydroxy-2-(di-n-propylamino)tetralin reduces striatal glutamate in an animal model of Parkinson’s disease. NeuroReport 16:699–703PubMedGoogle Scholar
  28. 28.
    Dupre KB, Eskow KL, Barnum CJ, Bishop C (2008) Striatal 5-HT(1A) receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat. Neuropharmacology 55:1321–1328PubMedCentralPubMedGoogle Scholar
  29. 29.
    Gil SJ, Park CH, Lee JE, Minn YK, Koh HC (2011) Positive association between striatal serotonin level and abnormal involuntary movements in chronic l-DOPA-treated hemiparkinsonian rats. Brain Res Bull 84(2):151–156PubMedGoogle Scholar
  30. 30.
    Conn PJ, Battaglia G, Marino MJ, Nicoletti F (2005) Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat Rev Neurosci 6:787–798PubMedGoogle Scholar
  31. 31.
    Finlay C, Duty S (2014) Therapeutic potential of targeting glutamate receptors in Parkinson’s disease. J Neural Transm 121(8):861–880PubMedGoogle Scholar
  32. 32.
    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(1):76–89PubMedGoogle Scholar
  33. 33.
    Picconi B, Pisani A, Centonze D, Battaglia G, Storto M, Nicoletti F, Bernardi G, Calabresi P (2002) Striatal metabotropic glutamate receptor function following experimental parkinsonism and chronic levodopa treatment. Brain 125:2635–2645PubMedGoogle Scholar
  34. 34.
    Samadi P, Grégoire L, Morissette M, Calon F, Hadj Tahar A, Bélanger N, Dridi M, Bédard PJ, Di Paolo T (2008) Basal ganglia group II metabotropic glutamate receptors specific binding in non-human primate model of l-Dopa-induced dyskinesias. Neuropharmacology 54:258–268PubMedGoogle Scholar
  35. 35.
    Rylander D, Recchia A, Mela F, Dekundy A, Danysz W, Cenci MA (2009) Pharmacological modulation of glutamate transmission in a rat model of l-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signaling. J Pharmacol Exp Ther 330(1):227–235PubMedCentralPubMedGoogle Scholar
  36. 36.
    Samadi P, Grégoire L, Morissette M, Calon F, Hadj Tahar A, Dridi M, Belanger N, Meltzer LT, Bédard PJ, Di Paolo T (2008) mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys. Neurobiol Aging 29:1040–1051PubMedGoogle Scholar
  37. 37.
    Ouattara B, Grégoire L, Morissette M, Gasparini F, Vranesic I, Bilbe G, Johns DR, Rajput A, Hornykiewicz O, Rajput AH, Gomez-Mancilla B, Di Paolo T (2011) Metabotropic glutamate receptor type 5 in levodopa-induced motor complications. Neurobiol Aging 32:1286–1295PubMedGoogle Scholar
  38. 38.
    Dekundy A, Pietraszek M, Schaefer D, Cenci MA, Danysz W (2006) Effects of group I metabotropic glutamate receptors blockade in experimental models of Parkinson’s disease. Brain Res Bull 69:318–326PubMedGoogle Scholar
  39. 39.
    Mela F, Marti M, Dekundy A, Danysz W, Morari M, Cenci MA (2007) Antagonism of metabotropic glutamate receptor type 5 attenuates l-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson’s disease. J Neurochem 101:483–497PubMedGoogle Scholar
  40. 40.
    Rylander D, Iderberg H, Li Q, Dekundy A, Zhang J, Li H, Baishen R, Danysz W, Bezard E, Cenci MA (2010) A mGluR5 antagonist under clinical development improves l-DOPA-induced dyskinesia in parkinsonian rats and monkeys. Neurobiol Dis 39:352–361PubMedGoogle Scholar
  41. 41.
    Dekundy A, Gravius A, Hechenberger M, Pietraszek M, Nagel J, Tober C, van der Elst M, Mela F, Parsons CG, Danysz W (2011) Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on L: -DOPA-induced dyskinesia. J Neural Transm 118:1703–1716PubMedGoogle Scholar
  42. 42.
    Grégoire L, Morin N, Ouattara B, Gasparini F, Bilbe G, Johns D, Vranesic I, Sahasranaman S, Gomez-Mancilla B, Di Paolo T (2011) The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in l-Dopa-treated parkinsonian monkeys. Parkinsonism Relat Disord 17:270–276PubMedGoogle Scholar
  43. 43.
    Morelli M, Carta AR, Jenner P (2009) Adenosine A2A receptors and Parkinson’s disease. Handb Exp Pharmacol 193:589–615PubMedGoogle Scholar
  44. 44.
    Calon F, Dridi M, Hornykiewicz O, Bedard PJ, Rajput AH, Di Paolo T (2004) Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain 127:1075–1084PubMedGoogle Scholar
  45. 45.
    Morissette M, Dridi M, Calon F, Hadj Tahar A, Meltzer LT, Bédard PJ, Di Paolo T (2006) Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: effect on adenosine A2A receptors. Synapse 60:239–250PubMedGoogle Scholar
  46. 46.
    Zeng BY, Pearce RK, MacKenzie GM, Jenner P (2000) Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with l-DOPA. Eur J Neurosci 12:1096–1104PubMedGoogle Scholar
  47. 47.
    Bibbiani F, Oh JD, Petzer JP, Castagnoli N Jr, Chen JF, Schwarzschild MA, Chase TN (2003) A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol 184:285–294PubMedGoogle Scholar
  48. 48.
    Phelps ME (2000) Positron emission tomography provides molecular imaging of biological processes. PNAS 97:9226–9233PubMedCentralPubMedGoogle Scholar
  49. 49.
    Loane C, Politis M (2011) Positron emission tomography neuroimaging in Parkinson’s disease. Am J Transl Res. 3(4):323–341PubMedCentralPubMedGoogle Scholar
  50. 50.
    Politis M, Piccini P (2012) Positron emission tomography imaging in neurological disorders. J Neurol 259:1769–1780PubMedGoogle Scholar
  51. 51.
    Politis M, Niccolini F (2015) Serotonin in Parkinson’s disease. Behav Brain Res 277:136–145Google Scholar
  52. 52.
    Niccolini F, Su P, Politis M (2014) Dopamine receptor mapping with PET imaging in Parkinson’s disease. J Neurol 261:2251–2263Google Scholar
  53. 53.
    Niccolini F, Loane C, Politis M (2014) Dyskinesias in Parkinson’s disease: views from positron emission tomography studies. Eur J Neurol 21(694–9):e39–e43Google Scholar
  54. 54.
    de la Fuente-Fernandez R, Lu JQ, Sossi V, Jivan S, Schulzer M, Holden JE, Lee CS, Ruth TJ, Calne DB, Stoessl AJ (2001) Biochemical variations in the synaptic levels of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 49:298–303PubMedGoogle Scholar
  55. 55.
    de la Fuente-Fernández R, Lim AS, Sossi V, Holden JE, Calne DB, Ruth TJ, Stoessl AJ (2001) Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. J Cereb Blood Flow Metab 21:1151–1159Google Scholar
  56. 56.
    de la Fuente-Fernandez R, Sossi V, Huang Z, Furtado S, Lu QR, Calne DB, Ruth TJ, Stoessl AJ (2004) Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias. Brain 127:2747–2754PubMedGoogle Scholar
  57. 57.
    Pavese N, Evans AH, Tai YF, Hotton G, Brooks DJ, Lees AJ, Piccini P (2006) Clinical correlates of levodopa induced dopamine release in Parkinson’s disease: a PET study. Neurology 67:1612–1617PubMedGoogle Scholar
  58. 58.
    Politis M, Wu K, Loane C, Brooks DJ, Kiferle L, Turkheimer FE, Bain P, Molloy S, Piccini P (2014) Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients. J Clin Invest 124:1340–1349PubMedCentralPubMedGoogle Scholar
  59. 59.
    Goetz CG, Laska E, Hicking C, Damier P, Müller T, Nutt J, Warren Olanow C, Rascol O, Russ H (2008) Placebo influences on dyskinesia in Parkinson’s disease. Mov Disord 23:700–707PubMedCentralPubMedGoogle Scholar
  60. 60.
    Müller T, Olanow CW, Nutt J (2006) The PADDY-2 study: the evaluation of sarizotan for treatment-associated dyskinesia in Parkinson’s disease patients. Mov Disord 21(Suppl 15):S591Google Scholar
  61. 61.
    Goetz CG, Damier P, Hicking C, Laska E, Müller T, Olanow CW, Rascol O, Russ H (2007) Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord 22:179–186PubMedGoogle Scholar
  62. 62.
    Hagell P, Piccini P, Björklund A, Brundin P, Rehncrona S, Widner H, Crabb L, Pavese N, Oertel WH, Quinn N, Brooks DJ, Lindvall O (2002) Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci 5:627–628PubMedGoogle Scholar
  63. 63.
    Ma Y, Feigin A, Dhawan V, Fukuda M, Shi Q, Greene P, Breeze R, Fahn S, Freed C, Eidelberg D (2002) Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann Neurol 52:628–634PubMedGoogle Scholar
  64. 64.
    Olanow CW, Gracies JM, Goetz CG, Stoessl AJ, Freeman T, Kordower JH, Godbold J, Obeso JA (2009) Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in Parkinson’s disease: a double blind video-based analysis. Mov Disord 24:336–343PubMedGoogle Scholar
  65. 65.
    Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, Bjorklund A, Lindvall O, Piccini P (2010) Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med 2:38–46Google Scholar
  66. 66.
    Politis M (2010) Dyskinesias after neural transplantation in Parkinson’s disease: what do we know and what is next? BMC Med 8:80PubMedCentralPubMedGoogle Scholar
  67. 67.
    Politis M, Oertel WH, Wu K, Quinn NP, Pogarell O, Brooks DJ, Bjorklund A, Lindvall O, Piccini P (2011) Graft-induced dyskinesias in Parkinson’s disease: high striatal serotonin/dopamine transporter ratio. Mov Disord 26:1997–2003PubMedGoogle Scholar
  68. 68.
    Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Oertel WH, Björklund A, Lindvall O, Piccini P (2012) Serotonin neuron loss and nonmotor symptoms continue in Parkinson’s patients treated with dopamine grafts. Sci Transl Med 4:128–141Google Scholar
  69. 69.
    Politis M, Piccini P (2010) Brain imaging after neural transplantation. Prog Brain Res 184:193–203PubMedGoogle Scholar
  70. 70.
    Politis M, Piccini P (2012) In vivo imaging of the integration and function of nigral grafts in clinical trials. Prog Brain Res 2000:199–220Google Scholar
  71. 71.
    Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, Widner H, Rehncrona S, Brundin P, Björklund A, Lindvall O, Limousin P, Quinn N, Foltynie T (2014) Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol 71:83–87PubMedCentralPubMedGoogle Scholar
  72. 72.
    Loane C, Politis M (2012) Buspirone: what is it all about? Brain Res 21(1461):111–118Google Scholar
  73. 73.
    Duty S (2012) Targeting glutamate receptors to tackle the pathogenesis, clinical symptoms and levodopa-induced dyskinesia associated with Parkinson’s disease. CNS Drugs 26:1017–1032PubMedGoogle Scholar
  74. 74.
    Ahmed I, Bose S, Pavese N, Ramlackhansingh A, Turkheimer F, Hotton G, Hammers A, Brooks DJ (2011) Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain 134:979–986PubMedGoogle Scholar
  75. 75.
    Crosby NJ, Deane K, Clarke CE (2003) Amantadine for dyskinesia in Parkinson’s disease. Cochrane Database Syst Rev 2:CD003467PubMedGoogle Scholar
  76. 76.
    Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN (1998) Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 50:1323–1326PubMedGoogle Scholar
  77. 77.
    Luginger E, Wenning GK, Bösch S, Poewe W (2000) Beneficial effects of amantadine on l-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord 15:873–878PubMedGoogle Scholar
  78. 78.
    Snow BJ, Macdonald L, Mcauley D, Wallis W (2000) The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 23:82–85PubMedGoogle Scholar
  79. 79.
    Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M (2004) Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatr 75:141–143PubMedCentralPubMedGoogle Scholar
  80. 80.
    Berg D, Godau J, Trenkwalder C, Eggert K, Csoti I, Storch A, Huber H, Morelli-Canelo M, Stamelou M, Ries V, Wolz M, Schneider C, Di Paolo T, Gasparini F, Hariry S, Vandemeulebroecke M, Abi-Saab W, Cooke K, Johns D, Gomez-Mancilla B (2011) AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord 26:1243–1250PubMedGoogle Scholar
  81. 81.
    Stocchi F, Rascol O, Destee A, Hattori N, Hauser RA, Lang AE, Poewe W, Stacy M, Tolosa E, Gao H, Nagel J, Merschhemke M, Graf A, Kenney C, Trenkwalder C (2013) AFQ056 in Parkinson patients with l-DOPA-induced dyskinesia: 13-week dose-finding study. Mov Disord 28:1838–1846PubMedGoogle Scholar
  82. 82.
    Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, Hashimoto M, Ishibashi K, Oda K, Sakata M, Hamamoto M, Kobayashi S, Katayama Y, Ishii K (2011) Adenosine A2A receptors measured with [11C]TMSX PET in the striata of Parkinson’s disease patients. PLoS One 6:e17338PubMedCentralPubMedGoogle Scholar
  83. 83.
    Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ (2011) Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology 76:1811–1816PubMedCentralPubMedGoogle Scholar
  84. 84.
    Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M, Japanese Istradefylline Study Group (2010) Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord 25:1437–1443PubMedGoogle Scholar
  85. 85.
    Pourcher E, Fernandez HH, Stacy M, Mori A, Ballerini R, Chaikin P (2012) Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord 18:178–184PubMedGoogle Scholar
  86. 86.
    Hauser RA, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M, Huyck S, Wolski K (2011) Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 10:221–229PubMedGoogle Scholar
  87. 87.
    Samadi P, Bedard PJ, Rouillard C (2006) Opioids and motor complications in Parkinson’s disease. Trends Pharmacol Sci 27:512–517PubMedGoogle Scholar
  88. 88.
    Piccini P, Ra Weeks, Brooks DJ (1997) Alterations in opioid receptor binding in Parkinson’s disease patients with levodopa-induced dyskinesias. Ann Neurol 42:720–726PubMedGoogle Scholar
  89. 89.
    Sadzot B, Price JC, Mayberg HS, Douglass KH, Dannals RF, Lever JR, Ravert HT, Wilson AA, Wagner HN Jr, Feldman MA (1992) Quantification of human opiate receptor concentration and affinity using high and low specific activity [11C]diprenorphine and positron emission tomography. J Cereb Blood Flow Metab 12:885Google Scholar
  90. 90.
    Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in the rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  91. 91.
    Mailleux P, Vanderhaeghen JJ (1992) Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons. Neurosci Lett 148:173–176PubMedGoogle Scholar
  92. 92.
    Glass M, Dragunow M, Faull RLM (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318PubMedGoogle Scholar
  93. 93.
    Martín AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M, de Fonseca FR, Moratalla R (2008) Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors. Neuropsychopharmacology 33:1667–1679PubMedGoogle Scholar
  94. 94.
    van Laere K, Casteels C, Lunskens S, Goffin K, Grachev ID, Bormans G, Vandenberghe W (2012) Regional changes in type 1 cannabinoid receptor availability in Parkinson’s disease in vivo. Neurobiol Aging 33:620PubMedGoogle Scholar
  95. 95.
    Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM (2001) Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 57:2108–2111PubMedGoogle Scholar
  96. 96.
    Venderová K, Růzicka E, Vorísek V, Visnovský P (2004) Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms. Mov Disord 19:1102–1106PubMedGoogle Scholar
  97. 97.
    Zhou FM, Wilson CJ, Dani JA (2002) Cholinergic interneuron characteristics and nicotinic properties in the striatum. J Neurobiol 53:590–605PubMedGoogle Scholar
  98. 98.
    Kitabatake Y, Hikida T, Watanabe D, Pastan I, Nakanishi S (2003) Impairment of reward-related learning by cholinergic cell ablation in the striatum. Proc Natl Acad Sci USA 100:7965–7970PubMedCentralPubMedGoogle Scholar
  99. 99.
    Nelson AB, Hammack N, Yang CF, Shah NM, Seal RP, Kreitzer AC (2014) Striatal cholinergic interneurons Drive GABA release from dopamine terminals. Neuron 82(1):63–70PubMedCentralPubMedGoogle Scholar
  100. 100.
    Quik M, Cox H, Parameswaran N, O’Leary K, Langston JW, Di Monte D (2007) Nicotine reduces levodopa-induced dyskinesias in lesioned monkeys. Ann Neurol 62:588–596PubMedGoogle Scholar
  101. 101.
    Bordia T, Campos C, Huang L, Quik M (2008) Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias in a rat model of Parkinson’s disease. J Pharmacol Exp Ther 327:239–247PubMedGoogle Scholar
  102. 102.
    Huang L, Grady SR, Quik M (2011) Nicotine reduces l-DOPA-induced dyskinesias by acting at beta2 nicotinic receptors. J Pharmacol Exp Ther 338:932–941PubMedCentralPubMedGoogle Scholar
  103. 103.
    Quik M, Mallela A, Ly J, Zhang D (2013) Nicotine reduces established levodopa-induced dyskinesias in a monkey model of Parkinson’s disease. Mov Disord 28:1398–1406PubMedCentralPubMedGoogle Scholar
  104. 104.
    Zhang D, Mallela A, Sohn D, Carroll FI, Bencherif M, Letchworth S, Quik M (2013) Nicotinic receptor agonists reduce l-DOPA-induced dyskinesias in a monkey model of Parkinson’s disease. J Pharmacol Exp Ther 347:225–234PubMedCentralPubMedGoogle Scholar
  105. 105.
    Rinne JO, Myllykyla T, Lonnberg P, Marjamaki P (1991) A postmortem study of brain nicotinic receptors in Parkinson’s and Alzheimer’s disease. Brain Res 547:167–170PubMedGoogle Scholar
  106. 106.
    Quik M, Bordia T, Forno L, McIntosh JM (2004) Loss of alpha-conotoxinMII- and A85380-sensitive nicotinic receptors in Parkinson’s disease striatum. J Neurochem 88:668–679PubMedGoogle Scholar
  107. 107.
    Schmaljohann J, Gundisch D, Minnerop M, Bucerius J, Joe A, Reinhardt M, Guhlke S, Biersack HJ, Wullner U (2006) In vitro evaluation of nicotinic acetylcholine receptors with 2-[18F]F-A85380 in Parkinson’s disease. Nucl Med Biol 33:305–309PubMedGoogle Scholar
  108. 108.
    Kas A, Bottlaender M, Gallezot JD, Vidailhet M, Villafane G, Grégoire MC, Coulon C, Valette H, Dolle F, Ribeiro MJ, Hantraye P, Remy P (2009) Decrease of nicotinic receptors in the nigrostriatal system in Parkinson’s disease. J Cereb Blood Flow 29:1601–1608Google Scholar
  109. 109.
    German DC, Manaye KF, White CL III, Woodward DJ, McIntire DD, Smith WK, Kalaria RN, Mann DM (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32:667–676PubMedGoogle Scholar
  110. 110.
    Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341PubMedGoogle Scholar
  111. 111.
    Mavridis M, Degryse AD, Lategan AJ, Marien MR, Colpaert FC (1991) Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson’s disease. Neuroscience 41:507–523PubMedGoogle Scholar
  112. 112.
    Shin E, Rogers JT, Devoto P, Björklund A, Carta M (2014) Noradrenaline neuron degeneration contributes to motor impairments and development of l-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. Exp Neurol 257:25–38PubMedGoogle Scholar
  113. 113.
    Arai A, Tomiyama M, Kannari K, Kimura T, Suzuki C, Watanabe M, Kawarabayashi T, Shen H, Shoji M (2008) Reuptake of l-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson’s disease via norepinephrine transporter. Synapse 62:632–635PubMedGoogle Scholar
  114. 114.
    Gomez-Mancilla B, Bédard PJ (1993) Effect of nondopaminergic drugs on l-dopa-induced dyskinesias in MPTP-treated monkeys. Clin Neuropharmacol 16:418–427PubMedGoogle Scholar
  115. 115.
    Buck K, Ferger B (2010) The selective alpha1 adrenoceptor antagonist HEAT reduces l-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. Synapse 64:117–126PubMedGoogle Scholar
  116. 116.
    Lindenbach D, Ostock CY, Eskow Jaunarajs KL, Dupre KB, Barnum CJ, Bhide N, Bishop C (2011) Behavioral and cellular modulation of l-DOPA-induced dyskinesia by beta-adrenoceptor blockade in the 6-hydroxydopamine-lesioned rat. J Pharmacol Exp Ther 337:755–765PubMedCentralPubMedGoogle Scholar
  117. 117.
    Carpentier AF, Bonnet AM, Vidailhet M, Agid Y (1996) Improvement of levodopa-induced dyskinesia by propranolol in Parkinson’s disease. Neurology 46:1548–1551PubMedGoogle Scholar
  118. 118.
    Buck K, Voehringer P, Ferger B (2010) The alpha(2) adrenoceptor antagonist idazoxan alleviates l-DOPA induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6-hydroxydopamine-lesioned rats. J Neurochem 112:444–452PubMedGoogle Scholar
  119. 119.
    Fox SH, Henry B, Hill MP, Peggs D, Crossman AR, Brotchie JM (2001) Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the alpha(2) adrenoceptor antagonist idazoxan. Mov Disord 16:642–650PubMedGoogle Scholar
  120. 120.
    Grondin R, Hadj Tahar A, Doan VD, Ladure P, Bedard PJ (2000) Noradrenoceptor antagonism with idazoxan improves l-dopa-induced dyskinesias in MPTP monkeys. Naunyn Schmiedebergs Arch Pharmacol 361:181–186PubMedGoogle Scholar
  121. 121.
    Savola JM, Hill M, Engstrom M, Merivuori H, Wurster S, McGuire SG (2003) Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Mov Disord 18:872–883PubMedGoogle Scholar
  122. 122.
    Rascol O, Arnulf I, Peyro-Saint Paul H, Brefel-Courbon C, Vidailhet M, Thalamas C (2001) Idazoxan, an alpha-2 antagonist, and l-DOPA-induced dyskinesias in patients with Parkinson’s disease. Mov Disord 16:708–713PubMedGoogle Scholar
  123. 123.
    Lewitt PA, Hauser RA, Lu M, Nicholas AP, Weiner W, Coppard N, Leinonen M, Savola JM (2012) Randomized clinical trial of fipamezole for dyskinesia in Parkinson disease (FJORD study). Neurology 79:163–169PubMedGoogle Scholar
  124. 124.
    Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N, N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA 89:8155–8159PubMedCentralPubMedGoogle Scholar
  125. 125.
    Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151PubMedGoogle Scholar
  126. 126.
    Bordet R, Ridray S, Carboni S, Diaz J, Sokoloff P, Schwartz JC (1997) Induction of dopamine D3 receptor expression as a mechanism of behavioural sensitization to levodopa. Proc Natl Acad Sci USA 94:3363–3367PubMedCentralPubMedGoogle Scholar
  127. 127.
    Bezard E, Ferry S, Mach U, Stark H, Leriche L, Boraud T, Gross C, Sokoloff P (2003) Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 9:762–767PubMedGoogle Scholar
  128. 128.
    van Kampen JM, Stoessl AJ (2003) Effects of oligonucleotide antisense to dopamineD3 receptor mRNA in a rodent model of behavioural sensitization to levodopa. Neuroscience 116:307–314PubMedGoogle Scholar
  129. 129.
    Guigoni C, Aubert I, Li Q, Gurevich VV, Benovic JL, Ferry S, Mach U, Stark H, Leriche L, Håkansson K, Bioulac BH, Gross CE, Sokoloff P, Fisone G, Gurevich EV, Bloch B, Bezard E (2005) Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat Disord 11(Suppl. 1):S25–S29PubMedGoogle Scholar
  130. 130.
    Visanji NP, Fox SH, Johnston T, Reyes G, Millan MJ, Brotchie JM (2009) DopamineD3 receptor stimulation underlies the development of l-DOPA-induced dysk-inesia in animal models of Parkinson’s disease. Neurobiol Dis 35:184–192PubMedGoogle Scholar
  131. 131.
    Cote SR, Chitravanshi VC, Bleickardt C, Sapru HN, Kuzhikandathil EV (2014) Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors. Behav Brain Res 263:46–50PubMedGoogle Scholar
  132. 132.
    Kumar R, Riddle L, Griffin SA, Grundt P, Newman AH, Luedtke RR (2009) Evaluation of the D3 dopamine receptor selective antagonist PG01037 on l-dopa-dependent abnormal involuntary movements in rats. Neuropharmacology 56:944–955PubMedGoogle Scholar
  133. 133.
    Kumar R, Riddle LR, Griffin SA, Chu W, Vangveravong S, Neisewander J, Mach RH, Luedtke RR (2009) Evaluation of D2 and D3 dopamine receptor selective compounds on l-dopa-dependent abnormal involuntary movements in rats. Neuropharmacology 56:956–969PubMedCentralPubMedGoogle Scholar
  134. 134.
    Mela F, Millan MJ, Brocco M, Morari M (2010) The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect l-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats. Neuropharmacology 58:528–536PubMedGoogle Scholar
  135. 135.
    Rabiner EA, Slifstein M, Nobrega J, Plisson C, Huiban M, Raymond R, Diwan M, Wilson AA, McCormick P, Gentile G, Gunn RN, Laruelle MA (2009) In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: studies in non-human primates and transgenic mice. Synapse 63:782–793PubMedGoogle Scholar
  136. 136.
    Boileau I, Guttman M, Rusjan P, Adams JR, Houle S, Tong J, Hornykiewicz O, Furukawa Y, Wilson AA, Kapur S, Kish SJ (2009) Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson’s disease. Brain 132:1366–1375PubMedGoogle Scholar
  137. 137.
    Nishi A, Kuroiwa M, Shuto T (2011) Mechanisms for the modulation of dopamine d(1) receptor signaling in striatal neurons. Front Neuroanat 5:43PubMedCentralPubMedGoogle Scholar
  138. 138.
    Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5:660–670PubMedGoogle Scholar
  139. 139.
    Nishi A, Kuroiwa M, Miller DB, O’Callaghan JP, Bateup HS, Shuto T, Sotogaku N, Fukuda T, Heintz N, Greengard P, Snyder GL (2008) Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 28:10460–10471PubMedCentralPubMedGoogle Scholar
  140. 140.
    Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435–447PubMedGoogle Scholar
  141. 141.
    Girault JA (2012) Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol 970:407–429PubMedGoogle Scholar
  142. 142.
    Hossain MA, Weiner N (1993) Dopaminergic functional supersensitivity: effects of chronic l-dopa and carbidopa treatment in an animal model of Parkinson’s disease. J Pharmacol Exp Ther 267:1105–1111PubMedGoogle Scholar
  143. 143.
    Tenn CC, Niles LP (1997) Sensitization of G protein-coupled benzodiazepine receptors in the striatum of 6-hydroxydopamine-lesioned rats. J Neurochem 69:1920–1926PubMedGoogle Scholar
  144. 144.
    Giorgi M, D’Angelo V, Esposito Z, Nuccetelli V, Sorge R, Martorana A, Stefani A, Bernardi G, Sancesario G (2008) Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms. Eur J Neurosci 28:941–950PubMedGoogle Scholar
  145. 145.
    Picconi B, Centonze D, Håkansson K, Bernardi G, Greengard P, Fisone G, Cenci MA, Calabresi P (2003) Loss of bidirectional striatal synaptic plasticity in l-DOPA-induced dyskinesia. Nat Neurosci 6:501–506PubMedGoogle Scholar
  146. 146.
    Picconi B, Paillé V, Ghiglieri V, Bagetta V, Barone I, Lindgren HS, Bernardi G, Angela Cenci M, Calabresi P (2008) l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation. Neurobiol Dis 29:327–335PubMedGoogle Scholar
  147. 147.
    Picconi B, Bagetta V, Ghiglieri V, Paillè V, Di Filippo M, Pendolino V, Tozzi A, Giampà C, Fusco FR, Sgobio C, Calabresi P (2011) Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia. Brain 134:375–387PubMedGoogle Scholar
  148. 148.
    Cenci MA (2010) Pathophysiology of l-DOPA-induced dyskinesia in parkinson’s disease. In: Dunnett S, Björklund A, Iversen L, Iversen S (eds) Dopamine Handbook. Oxford University Press, New York, pp 434–444Google Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Flavia Niccolini
    • 1
  • Lorenzo Rocchi
    • 1
  • Marios Politis
    • 1
  1. 1.Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN)King’s College LondonLondonUK

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