Journal of Neural Transmission

, Volume 115, Issue 3, pp 431–441 | Cite as

Pharmacological treatment of Parkinson’s disease: life beyond dopamine D2/D3 receptors?

  • G. Linazasoro
  • N. Van Blercom
  • L. Ugedo
  • J. A. Ruiz Ortega
Review Article


Parkinson’s disease (PD) is a multisystemic disorder in which several neurotransmitters other than dopamine are affected. Drugs acting on non-dopaminergic systems are envisaged as promising agents to treat PD and levodopa-induced dyskinesias (LID). However, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems have been assessed in human studies showing negative, inconsistent or unsatisfactory results. Most of these drugs had been tested previously in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, as well as in the classic 6-hydroxydopamine-lesioned rat model. These failures raise several questions and concerns about the true reliability of animal studies, the adequacy of the working hypotheses and design of clinical trials, the validity of tools in current use to evaluate a particular effect, and the selectivity of the drugs used. More importantly, observed discrepancies between the results in models and patients, could challenge the validity of current ideas about the pathophysiology of parkinsonism and LID.

Keywords: Parkinson’s disease; levodopa-induced dyskinesias; non-dopaminergic drugs; animal models 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agid, Y, Graybiel, AM, Ruberg, M, Hirsch, E, Blin, J, Dubois, B, Javoy-Agid, F 1990The efficacy of levodopa treatment declines in the course of Parkinson’s disease: do nondopaminergic lesions play a role?Adv Neurol5383100PubMedGoogle Scholar
  2. Bara-Jimenez, W, Dimitrova, T, Sherzai, A, Favit, A, Mouradian, MM, Chase, TN 2004Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson’s diseaseMov Disord1911831186PubMedCrossRefGoogle Scholar
  3. Bara-Jimenez, W, Bibbiani, F, Morris, MJ,  et al. 2005Effects of serotonin 5HT1A agonist in advanced Parkinson’s diseaseMov Disord20932936PubMedCrossRefGoogle Scholar
  4. Baronti, F, Mouradian, MM, Conant, KE,  et al. 1992Partial dopamine agonist therapy of levodopa-induced dyskinesiasNeurology4212411243PubMedGoogle Scholar
  5. Bartoszyk, GD, van Amsterdam, C, Greiner, HE, Rautenberg, W, Russ, H, Seyfried, CA 2004Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. Neurochemical profileJ Neural Transm111113126PubMedCrossRefGoogle Scholar
  6. Beal, MF 2001Experimental models of Parkinson’s diseaseNat Rev Neurosci2325332PubMedCrossRefGoogle Scholar
  7. Bennett, JP,Jr, Landow, ER, Dietrich, S, Schuh, LA 1994Suppression of dyskinesias in advanced Parkinson’s disease: moderate daily clozapine doses provide long-term dyskinesia reductionMov Disord9409414PubMedCrossRefGoogle Scholar
  8. Bezard, E, Ferry, S, Mach, U,  et al. 2003Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor functionNat Med9762777PubMedCrossRefGoogle Scholar
  9. Bibbiani, F, Oh, JD, Chase, TN 2001Serotonin 5HT1A agonist improves motor complications in rodent and primate parkinsonian modelsNeurology5718291834PubMedGoogle Scholar
  10. Bonifati, V, Fabrizio, E, Cipriani, R, Vanacore, N, Meco, G 1994Buspirone in levodopa-induced dyskinesiasClin Neuropharmacol177382PubMedCrossRefGoogle Scholar
  11. Bracco, F Battaglia, A Chouza, C PKDS009 Study Group2004The long-acting dopamine receptor agonist cabergoline in early Parkinson’s disease: final results of a 5-year, double-blind, levodopa-controlled studyCNS Drugs18733746PubMedCrossRefGoogle Scholar
  12. Braz, CA, Borges, V, Ferraz, HB 2004Effect of riluzole on dyskinesia and duration of the on state in Parkinson’s disease patients: a double-blind, placebo-controlled pilot studyClin Neuropharmacol272529PubMedCrossRefGoogle Scholar
  13. Brotchie, JM 2003CB1 cannabinoid receptor signalling in Parkinson’s diseaseCurr Opin Pharmacol35461PubMedCrossRefGoogle Scholar
  14. Calon, F, Rajput, AH, Hornykiewicz, O, Bedard, PJ, Di Paolo, T 2003Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson’s diseaseNeurobiol Dis14404416PubMedCrossRefGoogle Scholar
  15. Carroll, CB, Bain, PG, Teare, L,  et al. 2004Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover studyNeurology6312451250PubMedGoogle Scholar
  16. Cenci, MA, Whishaw, IQ, Schallert, T 2002Animal models of neurological deficits: how relevant is the rat?Nat Rev Neurosci3574579PubMedCrossRefGoogle Scholar
  17. Chaná, P, de Marinis, A, Barrientos, N 1997Gabapentin and motor fluctuations in Parkinson’s diseaseMov Disord12608PubMedCrossRefGoogle Scholar
  18. Chase, TN, Oh, JD 2000Striatal mechanisms and pathogenesis of parkinsonian signs and motor complicationsAnn Neurol47S122S130PubMedGoogle Scholar
  19. Chung, KA, Carlson, NE, Nutt, JG 2005Short-term paroxetine treatment does not alter the motor response to levodopa in PDNeurology6417971798PubMedCrossRefGoogle Scholar
  20. Collins, MO, Husi, H, Yu, L,  et al. 2006Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteomeJ Neurochem971623PubMedCrossRefGoogle Scholar
  21. Doder, M, Rabiner, EA, Turjanski, N, Lees, Aj, Brooks, DJ 2003Tremor in Parkinson’s disease and serotoninergic dysfunction: an (11)C-WAY 100635 PET studyNeurology60601605PubMedGoogle Scholar
  22. Durif, F, Vidailhet, M, Bonnet, AM,  et al. 1995Levodopa-induced dyskinesias are improved by fluoxetineNeurology4518551858PubMedGoogle Scholar
  23. Durif, F, Debilly, B, Galitzky, M,  et al. 2004Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled studyNeurology62381388PubMedGoogle Scholar
  24. Fernandez, HH 2006Istradefylline for the treatment of motor response complications on levodopa in PD: results of the KW-6002-US-018 study focusing on functional and notor improvementMov Disord21S642Google Scholar
  25. Fox, SH, Henry, B, Hill, MP,  et al. 2001Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the alpha-2 adrenoceptor antagonist idazoxanMov Disord16642650PubMedCrossRefGoogle Scholar
  26. Fox, SH, Lang, AE, Brotchie, JM 2006Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase Iia clinical studies: keys to success and roads to failureMov Disord2115781594PubMedCrossRefGoogle Scholar
  27. Frackiewicz, EJ, Jhee, SS, Shiovitz, TM,  et al. 2002Brasofensine treatment for Parkinson’s disease in combination with levodopa/carbidopaAnn Pharmacother36225230PubMedCrossRefGoogle Scholar
  28. Goetz, CG, Damier, P, Hicking, C, Laska, E, Müller, T, Olanow, CW, Rascol, O, Russ, H 2007Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trialMov Disord22179186PubMedCrossRefGoogle Scholar
  29. Gomez-Mancilla, B, Bedard, PJ 1993Effect of nondopaminergic drugs on L-dopa-induced dyskinesias in MPTP-treated monkeysClin Neuropharmacol16418427PubMedGoogle Scholar
  30. Guttman, M 2006Efficacy of istradefylline in Parkinson’s disease patients treated with levodopa with motor response complications: primary efficacy results of the KW-6002-US-018 studyMov Disord21S585Google Scholar
  31. Hauser, RA 2006Efficacy of istradefylline in levodopa-treated Parkinson’s disease patients with motor response complications: secondary efficacy results of the KW-6002-US-013 studyMov Disord21S510Google Scholar
  32. Hauser, R Hubble, JP Truong, DD the Istradefylline US-001 Study Group2003Randomized trial of the Adenosine A2A receptor antagonist istradefylline in advanced PDNeurology61297303PubMedGoogle Scholar
  33. Henry, B, Fox, SH, Peggs, D,  et al. 1999The alpha 2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of levodopa in the MPTP-lesioned primate model of Parkinson’s diseaseMov Disord14744753PubMedCrossRefGoogle Scholar
  34. Henry, B, Fox, SH, Crossman, AR, Brotchie, JM 2001Mu- and delta-Opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s diseaseExp Neurol171139146PubMedCrossRefGoogle Scholar
  35. Hughes, NR, McKnight, AT, Woodruff, GN,  et al. 1998Kappa-opioid receptor agonists increase locomotor activity in the monoamine depleted rat model of parkinsonismMov Disord13228233PubMedCrossRefGoogle Scholar
  36. Imbert, C, Bezard, E, Guitraud, S, Boraud, T, Gross, CE 2000Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the macaque monkeyJ Neurosci Meth967176CrossRefGoogle Scholar
  37. Jenner, P 2003The contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson’s diseaseParkinsonism Relat D9131137CrossRefGoogle Scholar
  38. Johnston, TH, Brotchie, JM 2006Drugs in development for Parkinson’s diseaseCurr Opin Invest Drugs72532Google Scholar
  39. Kanda, T, Jackson, MJ, Smith, LA,  et al. 1998Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeysAnn Neurol43507513PubMedCrossRefGoogle Scholar
  40. Katzenschlager, R, Manson, AJ, Evans, A, Watt, H, Lees, AJ 2004Low dose quetiapine for drug induced dyskinesias in Parkinson’s disease: a double blind cross over studyJ Neurol Neurosurg Psychiatry75295297PubMedGoogle Scholar
  41. Klintenberg, R, Svenningsson, P, Gunne, L, Andren, PE 2002Naloxone reduces levodopa-induced dyskinesias and apomorphine-induced rotations in primate models of parkinsonismJ Neural Transm10912951307PubMedCrossRefGoogle Scholar
  42. Klockgether, T, Turski, L 1993Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal gangliaAnn Neurol34585593PubMedCrossRefGoogle Scholar
  43. Lees, AJ, Shaw, KM, Stern, G 1978Baclofen in Parkinson’s diseaseJ Neurol Neurosurg Psychiatry41707708PubMedGoogle Scholar
  44. Linazasoro, G 2004Recent failures of new potential symptomatic treatments for Parkinson’s disease: causes and solutionsMov Disord19743754PubMedCrossRefGoogle Scholar
  45. Lozano, AM, Carella, F 2002Physiologic studies in the human brain in movement disordersParkinsonism Relat Disord8455458PubMedCrossRefGoogle Scholar
  46. Lyons, KE, Pahwa, R 2006Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesiaClin Neuropharmacol29148153PubMedCrossRefGoogle Scholar
  47. Mailman, R, Huang, X, Nichols, DE 2001Parkinson’s disease and D1 dopamine receptorsCurr Opin Invest Drugs215821591Google Scholar
  48. Manson, AJ, Iakovidou, E, Lees, AJ 2000Idazoxan is ineffective for levodopa-induced dyskinesias in Parkinson’s diseaseMov Disord15336337PubMedCrossRefGoogle Scholar
  49. Manson, AJ, Katzenschlager, R, Hobart, J,  et al. 2001High dose naltrexone for dyskinesias induced by levodopaJ Neurol Neurosurg Psychiatry70554556PubMedCrossRefGoogle Scholar
  50. Mercuri, NB, Bernardi, G 2005The ‘magic’ of l-dopa: why is it the gold standard Parkinson’s disease therapy?Trends Pharmacol Sci26341344PubMedCrossRefGoogle Scholar
  51. Merello, M, Nouzeilles, MI, Cammarota, A, Leiguarda, R 1999Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized studyClin Neuropharmacol22273276PubMedGoogle Scholar
  52. Merims, D, Ziv, I, Djaldetti, R,  et al. 1999Riluzole for levodopa-induced dyskinesias in advanced Parkinson’s diseaseLancet35317641765PubMedCrossRefGoogle Scholar
  53. Mesnage, V, Houeto, JL, Bonnet, AM,  et al. 2004Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson’s diseaseClin Neuropharmacol27108110PubMedCrossRefGoogle Scholar
  54. Murata, M, Horiuchi, E, Kanazawa, I 2001Zonisamide has beneficial effects on Parkinson’s disease patientsNeurosci Res41397399PubMedCrossRefGoogle Scholar
  55. Murata, M Hasegawa, K Kanazawa, I The Japan Zonisamide on PD Study Group2007Zonisamide improves motor function in Parkinson’s disease. A randomized, double-blind studyNeurology684550PubMedCrossRefGoogle Scholar
  56. Nichols, NF, Cimini, MG, Haas, JV,  et al. 2002PNU-96391A (OSU6162) antagonizes the development of behavioural sensitization induced by dopamine agonists in a rat model for Parkinson’s diseaseNeuropharmacology43817824PubMedCrossRefGoogle Scholar
  57. Olanow, CW, Damier, P, Goetz, CG,  et al. 2004Multicenter, open-label, trial of sarizotan in Parkinson’s disease patients with levodopa-induced dyskinesias (the SPLENDID study)Clin Neuropharmacol275862PubMedCrossRefGoogle Scholar
  58. Olson, WL, Gruenthal, M, Mueller, ME, Olson, WH 1997Gabapentin for parkinsonism: a double-blind, placebo-controlled, crossover trialAm J Med1026066PubMedCrossRefGoogle Scholar
  59. Parkinson Study Group2000Pramipexole vs levodopa as initial therapy for Parkinson’s disease: a randomized controlled trialJAMA28419311938CrossRefGoogle Scholar
  60. Parkinson Study Group2001A randomized, controlled trial of remacemide for motor fluctuations in Parkinson’s diseaseNeurology56455462Google Scholar
  61. Pourcher, E 2006Safety and tolerability of istradefylline in Parkinson’s disease with motor response complications: results of the KW-6002-US-018 studyMov Disord21S508Google Scholar
  62. Qiu, J 2007Debates on translational research: a balancing actLancet Neurol6208209PubMedCrossRefGoogle Scholar
  63. Rascol, O, Fabre, N, Blin, O,  et al. 1994Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson’s diseaseMov Disord9437440PubMedCrossRefGoogle Scholar
  64. Rascol, O, Blin, O, Thalamas, C,  et al. 1999ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson’s diseaseAnn Neurol45736741PubMedCrossRefGoogle Scholar
  65. Rascol, O, Brooks, DJ, Korczyn, AD, De Deyn, PP, Clarke, CE, Lang, AE 2000A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopaN Eng J Med34214841491CrossRefGoogle Scholar
  66. Rascol, O, Arnulf, I, Peyro-Saint, PH,  et al. 2001aIdazoxan, an α-2 antagonist, and L-dopa-induced dyskinesias in patients with Parkinson’s diseaseMov Disord16708713CrossRefGoogle Scholar
  67. Rascol, O, Nutt, J, Blin, O,  et al. 2001bInduction by D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson’s diseaseArch Neurol58249254CrossRefGoogle Scholar
  68. Rascol, O, Lees, AJ, Poewe, W, Stalin, L 2006NS2330, a dopamine reuptake inhibitor, in levodopa-treated patients with Parkinson’s disease and motor fluctuations: the Phase II ADVANS studyMov Disord21S515Google Scholar
  69. Richard, IH, Maughn, A, Kurlan, R 1999Do serotonin reuptake inhibitor antidepressants worsen Parkinson’s disease? A retrospective case seriesMov Disord14155157PubMedCrossRefGoogle Scholar
  70. Richardson, PJ, Kase, H, Jenner, PG 1997Adenosine A2a receptor antagonists as new agents for the treatment of Parkinson’s diseaseTrends Pharmacol Sci18338344PubMedGoogle Scholar
  71. Samadi, P, Gregoire, L, Bedard, PJ 2003Opioid antagonists increase the dyskinetic response to dopaminergic agents in parkinsonian monkeys: interaction between dopamine and opioid systemsNeuropharmacology45954963PubMedCrossRefGoogle Scholar
  72. Sandyk, R, Snider, SR 1986Naloxone treatment of L-dopa-induced dyskinesias in Parkinson’s diseaseAm J Psychiatry143118PubMedGoogle Scholar
  73. Sañudo-Pena, MC, Tsou, K, Walker, JM 1999Motor actions of cannabinoids in the basal ganglia output nucleiLife Sci65703713PubMedCrossRefGoogle Scholar
  74. Savola, JM, Hill, M, Engstrom, M,  et al. 2003Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s diseaseMov Disord18872883PubMedCrossRefGoogle Scholar
  75. Schapira, AHV, Bezard, E, Brotchie, J,  et al. 2006Novel pharmacological targets for the treatment of Parkinson’s diseaseNature Reviews Dug Discovery5845854CrossRefGoogle Scholar
  76. Schwarzschild, MA, Agnati, L, Fuxe, K, Chen, JF, Morelli, M 2006Targeting adenosine A2a receptors in Parkinson’s diseaseTrends Neurosciz29647654CrossRefGoogle Scholar
  77. Sherzai, A, Bara-Jimenez, W, Sherzai, A, Dimitrova, T,  et al. 2003Adenosine A2A antagonist treatment of Parkinson’s diseaseNeurology61293296PubMedGoogle Scholar
  78. Sieradzan, KA, Fox, SH, Hill, MP,  et al. 2001Cannabinoids reduce levodopa-induced dyskinesias in Parkinson’s disease: a pilot studyNeurology5721082111PubMedGoogle Scholar
  79. Silverdale MA, Millan MJ, Crossman AR, Brotchie JM (2002) Dopamine D3 receptor blockade, and not stimulation, is associated with anti-parkinsonian activity in the MPTP-lesioned, non-human primate model of Parkinson’s disease. Soc Neurosci Abstr: S63.001Google Scholar
  80. Tan, LC, Protell, PH, Langston, JW, Togasaki, DM 2002The hyperkinetic abnormal movements scale: a tool for measuring levodopa-induced abnormal movements in squirrel monkeysMov Disord17902909PubMedCrossRefGoogle Scholar
  81. Thomas, A, Iacono, D, Luciano, AL, Armellino, K, Di Iorio, A, Onofrj, M 2004Duration of amantadine benefit on dyskinesia of severe Parkinson’s diseaseJ Neurol Neurosurg Psychiatry75141143PubMedGoogle Scholar
  82. Trugman, JM 2006Efficacy of istradefylline in levodopa-treated Parkinson’s disease patients with motor response complications: primary efficacy results of the KW-6002-US-013 studyMov Disord21S513Google Scholar
  83. Turjanski, N, Lees, AJ 1992Gamma vinyl GABA in the treatment of levodopa-induced dyskinesiasJ Neurol Neurosurg Psychiatry55413PubMedCrossRefGoogle Scholar
  84. Ueda, Y, Doi, T, Tokumaru, J, Willmore, LJ 2003Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizuresBrain Res Mol Brain Res11616PubMedCrossRefGoogle Scholar
  85. Van Blercom, N, Lasa, A, Verger, K,  et al. 2004Effects of gabapentin on the motor response to levodopa: a double-blind, placebo-controlled, crossover study in patients with complicated Parkinson’s diseaseClin Neuropharmacol27124128PubMedCrossRefGoogle Scholar
  86. Vergahen Metman, L, Blanchet, PJ, van den Munckhof, P,  et al. 1998aA trial of dextromethorphan in parkinsonian patients with motor response complicationsMov Disord13414417CrossRefGoogle Scholar
  87. Vergahen Metman, L, Del Dotto, P, van den Munckhof, P,  et al. 1998bAmantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s diseaseNeurology5013231326Google Scholar
  88. Verhagen Metman, L, Del Dotto, P, LePoole, K,  et al. 1999Amantadine for levodopa-induced dyskinesias: a 1-year follow-up studyArch Neurol5613831386CrossRefGoogle Scholar
  89. Visanji, NP, Gómez-Ramírez, J, Johnston, TH, Pires, D, Voon, V, Brotchie, JM, Fox, SH 2006Pharmacological characterization of psychosis-like behaviour in the MPTP-lesioned nonhuman primate model of Parkinson’s diseaseMov Disord2118791891PubMedCrossRefGoogle Scholar
  90. Williams, M, Wright, S, Lloyd, GK 1997Improved therapies for Parkinson’s disease: life beyond dopamine D2/D3 receptor agonistsTrends Pharmacol Sci18307310PubMedCrossRefGoogle Scholar
  91. Yoshida, S, Okada, M, Zhu, G, Kaneko, S 2005Effects of zonisamide on neurotransmitter exocytosis associated with ryanodine receptorsEpilepsy Res67153162PubMedCrossRefGoogle Scholar
  92. Zesiewicz, TA, Sullivan, KL, Maldonado, JL, Tatum, WO, Hauser, RA 2005Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson’s diseaseMov Disord2012051209PubMedCrossRefGoogle Scholar
  93. Ziegler, M, Fournier, V, Bathien, N,  et al. 1987Therapeutic response to progabide in neuroleptic- and L-dopa-induced dyskinesiasClin Neuropharmacol10238246PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • G. Linazasoro
    • 1
  • N. Van Blercom
    • 1
  • L. Ugedo
    • 2
  • J. A. Ruiz Ortega
    • 2
  1. 1.Centro de Investigación ParkinsonPoliclínica GipuzkoaSan SebastiánSpain
  2. 2.Department of Pharmacology, Faculty of MedicineUniversity of the Basque CountryLeioa

Personalised recommendations