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The Significance of Continuous Dopaminergic Stimulation in the Treatment of Parkinson’s Disease

Drugs volume 55, pages 1–9 (1998)Cite this article

Summary

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson’s disease. No other drug matches its ability to suppress parkinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much because of a decline in efficacy against core symptoms, but rather because of a rise in adverse effects. Most common are the motor response complications that appear within a few years of treatment initiation and ultimately affect most parkinsonian patients. These progressively disabling complications include response fluctuations and abnormal involuntary movements.

Current evidence indicates that ‘wearing-off’ fluctuations, typically the first motor complication to become clinically evident, initially reflect the loss of buffering normally provided by striatal dopaminergic terminals. Thus, with increasing degeneration of the nigrostriatal system, swings in plasma levodopa concentrations associated with standard dosage regimens produce nonphysiological fluctuations in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sites downstream from the dopamine system and now appear to underlie the progressive worsening of ‘wearing-off’ phenomena as well as the eventual appearance of other response complications.

Chronic intermittent stimulation of normally tonically active dopaminergic receptors activates specific signalling cascades in striatal dopaminoceptive medium spiny neurons, and this evidently results in long term potentiation of the synaptic efficacy of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GABAergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, appear that medium spiny neuron function changes to favour the appearance of response fluctuations of the ‘on-off’ type and peak dose dyskinesias.

The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contributes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian patients but also prevents their development in animal models of Parkinson’s disease. Thus, pharmaceutical approaches that provide relatively continuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategies are currently under development, and include various methods to prolong the duration of action of levodopa as well as the use of transdermally administered or very long acting dopamine agonists.

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References

  1. Jenner P. The rationale for the use of dopamine agonists in Parkinson’s disease. Neurology 1995; 45 Suppl. 3: S6–12

    PubMed  Article  CAS  Google Scholar 

  2. Bernheimer H, Birkmayer W, Hornykiewicz O, et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973; 20: 415–55

    CAS  Google Scholar 

  3. Blanchet P, Bedard PJ, Britton DR, et al. Differential effect of selective D1 and D2 dopamine receptor agonists on levodopainduced dyskinesia in l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine-exposed monkeys. J Pharmacol Exp Ther 1993; 267: 275–9

    PubMed  CAS  Google Scholar 

  4. Domino EF, Sheng J. Relative potency and efficacy of some dopamine agonists with varying selectivities for D1 and D2 receptors in MPTP-induced hemiparkinsonian monkeys. J Pharmacol Exp Ther 1993; 265: 1387–91

    PubMed  CAS  Google Scholar 

  5. Ebadi M, Srinivasan SK, Baxi MD. Oxidative stress and antioxidant therapy in Parkinson’s disease. Prog Neurobiol 1996; 48(1): 1–19

    PubMed  Article  CAS  Google Scholar 

  6. Owen AD, Schapira AH, Jenner P, et al. Oxidative stress and Parkinson’s disease. Ann N Y Acad Sci 1996; 786: 217–23

    PubMed  Article  CAS  Google Scholar 

  7. Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 1996; 47 Suppl. 3: S161–70

    PubMed  Article  CAS  Google Scholar 

  8. Lange KW, Rausch WD, Gsell W, et al. Neuroprotection by dopamine agonists. J Neural Transm Suppl. 1994; 43: 183–201

    PubMed  CAS  Google Scholar 

  9. Carvey PM, Pieri S, Ling ZD. Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole. J Neural Transm 1997; 104: 209–28

    PubMed  Article  CAS  Google Scholar 

  10. Chase TN, Engber TM, Mouradian MM. Palliative and prophylactic benefits of continuously administered dopaminomimetics in Parkinson’s disease. Neurology 1994; 44 Suppl. 6: S15–18

    PubMed  CAS  Google Scholar 

  11. Rinne UK. Early combination of bromocriptine and levodopa in the treatment of Parkinson’s disease: a 5-year follow-up. Neurology 1987; 37: 826–8

    PubMed  Article  CAS  Google Scholar 

  12. Schultz W. Behavior-related activity of primate dopamine neurons. Rev Neurol (Paris) 1994; 150: 634–9

    CAS  Google Scholar 

  13. Melamed E, Hefti F, Wurtman RJ. Nonaminergic striatal neurons convert exogenous L-dopa to dopamine in parkinsonism. Ann Neurol 1980; 8: 558–63

    PubMed  Article  CAS  Google Scholar 

  14. Mouradian MM, Juncos JL, Fabrini G, et al. Motor fluctuations in Parkinson’s disease: pathogenic and therapeutic studies. Ann Neurol 1987; 22: 475–9

    PubMed  Article  CAS  Google Scholar 

  15. Mouradian MM, Heuser IJE, Baronti F, et al. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 1990; 27: 18–23

    PubMed  Article  CAS  Google Scholar 

  16. Mouradian MM, Heuser IJ, Baronti F, et al. Pathogenesis of dyskinesias in Parkinson’s disease. Ann Neurol 1989; 25: 523–6

    PubMed  Article  CAS  Google Scholar 

  17. Marsden CD, Parkes JD. Success and problems of long-term therapy in Parkinson’s disease. Lancet 1997; 2: 345–9

    Google Scholar 

  18. Mizuno Y, Mori H, Kondo T. Parkinson’s disease: from etiology to treatment. Intern Med 1995; 34: 1045–54

    PubMed  Article  CAS  Google Scholar 

  19. Peppe A, Dambrosia JM, Chase TN. Risk factors for motor response complications in L-dopa-treated parkinsonian patients. Adv Neurol 1993; 60: 698–702

    PubMed  CAS  Google Scholar 

  20. Fabbrini G, Juncos J, Mouradian MM, et al. Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson’s disease. Ann Neurol 1987; 21: 370–6

    PubMed  Article  CAS  Google Scholar 

  21. Fabbrini G, Mouradian MM, Juncos JL, et al. Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, parti. Ann Neurol 1988; 24: 366–71

    PubMed  Article  CAS  Google Scholar 

  22. Mouradian MM, Juncos JL, Fabrini G, et al. Motor fluctuations in Parkinson’s disease: central and pathophysiological mechanisms. Part II. Ann Neurol 1988; 24: 372–8

    Article  CAS  Google Scholar 

  23. Shoulson I, Glaubiger GA, Chase TN. On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975; 25: 1144–8

    PubMed  Article  CAS  Google Scholar 

  24. Papa SM, Engber TM, Kask AM, et al. Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 1994; 662: 69–74

    PubMed  Article  CAS  Google Scholar 

  25. Marin C, Papa SM, Engber TM, et al. MK801 prevents levodopa-induced motor response alterations in parkinsonian rats. Eur J Pharmacol 1996; 736: 202–5

    CAS  Google Scholar 

  26. Verhagen-Metman L, Locatelli ER, Bravi D, et al. Apomorphine responses in Parkinson’s disease and the pathogenesis of motor response complications. Neurology 1997; 48: 369–72

    PubMed  Article  CAS  Google Scholar 

  27. Engber TM, Susel Z, Kuo S, et al. Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats. Brain Res 1991; 552: 113–8

    PubMed  Article  CAS  Google Scholar 

  28. Engber TM, Boldry RC, Kuo S, et al. Dopaminergic modulation of striatal neuropeptides: differential effects of D1 and D2 receptor stimulation on somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin. Brain Res 1992; 581: 261–8

    PubMed  Article  CAS  Google Scholar 

  29. Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990; 250: 1429–32

    PubMed  Article  CAS  Google Scholar 

  30. Engber TM, Boldry RC, Chase TN. The kappa-opioid receptor agonist spiradoline differentially alters the rotational response to dopamine D1 and D2 agonists. Eur J Pharmacol 1991; 200: 171–3

    PubMed  Article  CAS  Google Scholar 

  31. Engber TM, Marin C, Susel Z, et al. Differential effects of chronic dopamine D-l and D-2 agonists on rotational behavior and dopamine receptor binding. Eur J Pharmacol 1993; 236: 385–93

    PubMed  Article  CAS  Google Scholar 

  32. Chase TN, Engber TM, Mouradian MM. Contribution of dopaminergic and glutamatergic mechanisms to the pathogenesis of motor response complications in Parkinson’s disease. Adv Neurol 1996; 69: 497–501

    PubMed  CAS  Google Scholar 

  33. Engber TM, Papa SM, Boldry RC, et al. NMDA receptor blockade reverses motor response alterations induced by levodopa. Neuroreport 1994; 5: 2586–8

    PubMed  Article  CAS  Google Scholar 

  34. Papa SM, Boldry RC, Engber TM, et al. Reversal of levodopainduced motor fluctuations in experimental parkinsonism by NMDA receptor blockade. Brain Res 1995; 701: 13–8

    PubMed  Article  CAS  Google Scholar 

  35. Kotter R. Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. Prog Neurobiol 1994; 44: 163–96

    PubMed  Article  CAS  Google Scholar 

  36. Papa SM, Chase TN. Levodopa induced dyskinesias improved by a glutamate antagonist in parkinsonian monkeys. Ann Neural 1996; 39: 574–8

    Article  CAS  Google Scholar 

  37. Blanchet PJ, Verhagen Metman L, Mouradian MM, et al. Acute pharmacologic blockade of dyskinesias in Parkinson’s disease. Mov Disord 1996; 11: 580–1

    PubMed  Article  CAS  Google Scholar 

  38. Verhagen Metman L, Blanchet PJ, Mouradian MM, et al. Dextromethorphan and levodopa combination therapy in Parkinson’s patients with response fluctuations. Mov Disord 1996; 11: 184

    Google Scholar 

  39. Huang CC, Gean PW. Cyclic adenosine-3′,5′-monophosphate potentiates the synaptic potential mediated by NMDA receptors in the amygdala. J Neurosci Res 1995; 40: 747–54

    PubMed  Article  CAS  Google Scholar 

  40. Oh JD, Del Dotto P, Chase TN. Protein kinase A inhibitor attenuates levodopa-induced motor response alterations in the hemi-parkinsonian rat. Neurosci Lett 1997; 228: 5–8

    PubMed  Article  CAS  Google Scholar 

  41. Baronti F, Mouradian MM, Davis TL, et al. Continuous lisuride effects on central dopaminergic mechanisms in Parkinson’s disease. Ann Neural 1992; 32: 776–81

    Article  CAS  Google Scholar 

  42. Roberts JW, Cora-Locatelli G, Bravi D, et al. Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa action in parkinsonian patients. Neurology 1993; 43: 2685–8

    PubMed  Article  CAS  Google Scholar 

  43. Ruottinen HM, Rinne UK. A double-blind pharmacokinetic and clinical dose-response study of entacapone as an adjuvant to levodopa therapy in advanced Parkinson’s disease. Clin Neuropharmacol 1996; 19: 283–96

    PubMed  Article  CAS  Google Scholar 

  44. Ahlskog JE, Wright KF, Muenter MD, et al. Adjunctive cabergoline therapy of Parkinson’s disease: comparison with placebo and assessment of dose responses and duration of effect. Clin Neuropharmacol 1996; 19: 202–12

    PubMed  Article  CAS  Google Scholar 

  45. Rinne UK, Bracco F, Chouza C, et al. Cabergoline in the treatment of early Parkinson’s disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group. Neurology 1997; 48: 363–8

    CAS  Google Scholar 

  46. Belluzzi JD, Domino EF, May JM, et al. N-0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson’s disease. Mov Disord 1994; 9: 147–54

    PubMed  Article  CAS  Google Scholar 

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  1. Experimental Therapeutics Branch, NINDS, NIH, Bethesda, Maryland, USA

    Thomas N. Chase

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Chase, T.N. The Significance of Continuous Dopaminergic Stimulation in the Treatment of Parkinson’s Disease. Drugs 55, 1–9 (1998). https://doi.org/10.2165/00003495-199855001-00001

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  • DOI: https://doi.org/10.2165/00003495-199855001-00001

Keywords

  • Levodopa
  • Dopamine Agonist
  • Cabergoline
  • Entacapone
  • Tolcapone