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Involvement of the Cholinergic System in Levodopa-Induced Dyskinesia

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Levodopa-Induced Dyskinesia in Parkinson's Disease

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Abstract

Although levodopa-induced dyskinesia (LID) in Parkinson’s disease arises because of aberrant dopaminergic transmission, extensive evidence indicates that nondopaminergic drugs may be useful in the suppression of these abnormal involuntary movements. Here, we review a compelling literature which suggests that drugs that act on the nicotinic cholinergic system are beneficial in reducing LID. Nicotine treatment decreased LID in several parkinsonian animal models including mice, rats, and monkeys using treatment modes that readily extend to human use (patch or oral administration). Nicotine decreased LID when given either before or several months after the start of levodopa treatment, with no tolerance to its beneficial effect during the course of the study (30 weeks). Work with nicotinic acetylcholine receptor (nAChR) null mutant mice shows that nicotine exerts its antidyskinetic effects by acting at nAChRs, with the α4β2, α6β2, and α7 receptor subtypes all contributing to the occurrence of LID. An involvement of multiple subtypes in LID is also supported by studies with drugs targeting select nAChR populations. Notably, nicotine and nAChR drugs did not worsen parkinsonism in any animal model. The mechanisms whereby nicotine and nAChR drugs reduce LID may involve long-term nAChR downregulation and/or desensitization followed by a decline in striatal dopamine release. In addition to its ability to reduce LID, nicotine also protects against nigrostriatal damage and has cognitive-enhancing and antidepressant effects. These combined properties suggest that nicotine and nAChR drugs may be of benefit in the management of LID in Parkinson’s disease.

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References

  1. Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM. The pharmacology of LEVODOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev. 2013;65:171–222.

    Article  PubMed  CAS  Google Scholar 

  2. Poewe W, Mahlknecht P, Jankovic J. Emerging therapies for Parkinson’s disease. Curr Opin Neurol. 2012;25:448–59.

    Article  PubMed  CAS  Google Scholar 

  3. Millar NS, Gotti C. Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology. 2009;56:237–46.

    Article  PubMed  CAS  Google Scholar 

  4. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89:73–120.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Kuryatov A, Lindstrom J. Expression of functional human alpha6beta2beta3* acetylcholine receptors in Xenopus laevis oocytes achieved through subunit chimeras and concatamers. Mol Pharmacol. 2011;79:126–40.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Harpsoe K, Hald H, Timmermann DB, Jensen ML, Dyhring T, Nielsen EO, et al. Molecular determinants of subtype-selective efficacies of cytisine and the novel compound NS3861 at heteromeric nicotinic acetylcholine receptors. J Biol Chem. 2013;288:2559–70.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Quik M, Wonnacott S. {alpha}6{beta}2* and {alpha}4{beta}2* nicotinic acetylcholine receptors as drug targets for Parkinson’s disease. Pharmacol Rev. 2011;63:938–66.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Bordia T, Campos C, Huang L, Quik M. Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (LEVODOPA)-induced dyskinesia in a rat model of Parkinson’s disease. J Pharmacol Exp Ther. 2008;327:239–47.

    Article  PubMed  CAS  Google Scholar 

  9. Bordia T, Campos C, McIntosh JM, Quik M. Nicotinic receptor-mediated reduction in Levodopa-induced dyskinesia may occur via desensitization. J Pharmacol Exp Ther. 2010;333:929–38.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Huang L, Grady SR, Quik M. Nicotine reduces levodopa-induced dyskinesia by acting at {beta}2 nicotinic receptors. J Pharmacol Exp Ther. 2011;338:932–41.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Quik M, Park KM, Hrachova M, Mallela A, Huang LZ, McIntosh JM, et al. Role for alpha6 nicotinic receptors in levodopa-induced dyskinesia in parkinsonian mice. Neuropharmacology. 2012;63:450–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Quik M, Campos C, Grady S. Multiple CNS nicotinic receptors mediate Levodopa-induced dyskinesia; studies with parkinsonian nicotinic receptor knockout mice. Biochem Pharmacol. 2013;86(8):1153–62.

    Article  PubMed  CAS  Google Scholar 

  13. Quik M, Cox H, Parameswaran N, O’Leary K, Langston JW, Di Monte D. Nicotine reduces levodopa-induced dyskinesia in lesioned monkeys. Ann Neurol. 2007;62:588–96.

    Article  PubMed  CAS  Google Scholar 

  14. Quik M, Mallela A, Chin M, McIntosh JM, Perez XA, Bordia T. Nicotine-mediated improvement in levodopa-induced dyskinesia in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function. Neurobiol Dis. 2013;50:30–41.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Quik M, Mallela A, Ly J, Zhang D. Nicotine reduces established Levodopa-induced dyskinesia in a monkey model of Parkinson’s disease. Mov Disord. 2013;28(10):1398–406.

    PubMed  CAS  PubMed Central  Google Scholar 

  16. Huang LZ, Campos C, Ly J, Carroll FI, Quik M. Nicotinic receptor agonists decrease Levodopa-induced dyskinesia most effectively in moderately lesioned parkinsonian rats. Neuropharmacology. 2011;60:861–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Zhang D, Mallela A, Sohn D, Carroll FI, Bencherif M, Letchworth S, Quik M. Nicotinic receptor agonists reduce L-dopa-induced dyskinesias in a monkey model of Parkinson’s disease. J Pharmacol Exp Ther 2013;347:225–235. PMCID 3781407.

    Google Scholar 

  18. Quik M, Campos C, Bordia T, Strachan JP, Zhang J, McIntosh JM, et al. alpha4beta2 nicotinic receptors play a role in the nAChR-mediated decline in levodopa-induced dyskinesia in parkinsonian rats. Neuropharmacology. 2013;71:191–203.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Johnston TH, Huot P, Fox SH, Koprich JB, Szeliga KT, James JW, et al. TC-8831, a nicotinic acetylcholine receptor agonist, reduces levodopa-induced dyskinesia in the MPTP macaque. Neuropharmacology. 2013;73:337–47.

    Article  PubMed  CAS  Google Scholar 

  20. Jenner P. Functional models of Parkinson’s disease: a valuable tool in the development of novel therapies. Ann Neurol. 2009;64:S16–29.

    Article  Google Scholar 

  21. Duty S, Jenner P. Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol. 2011;164:1357–91.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Iderberg H, Francardo V, Pioli EY. Animal models of LEVODOPA-induced dyskinesia: an update on the current options. Neuroscience. 2012;211:13–27.

    Article  PubMed  CAS  Google Scholar 

  23. Exley R, Maubourguet N, David V, Eddine R, Evrard A, Pons S, et al. Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine. Proc Natl Acad Sci U S A. 2011;108:7577–82.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Liu L, Zhao-Shea R, McIntosh JM, Gardner PD, Tapper AR. Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing alpha4 and alpha6 subunits. Mol Pharmacol. 2012;81:541–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Zhao-Shea R, Liu L, Soll LG, Improgo MR, Meyers EE, McIntosh JM, et al. Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology. 2011;36:1021–32.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Gotti C, Guiducci S, Tedesco V, Corbioli S, Zanetti L, Moretti M, et al. Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement. J Neurosci. 2010;30:5311–25.

    Article  PubMed  CAS  Google Scholar 

  27. Giniatullin R, Nistri A, Yakel JL. Desensitization of nicotinic ACh receptors: shaping cholinergic signaling. Trends Neurosci. 2005;28:371–8.

    Article  PubMed  CAS  Google Scholar 

  28. Picciotto MR, Addy NA, Mineur YS, Brunzell DH. It is not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol. 2008;84:329–42.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Wonnacott S, Sidhpura N, Balfour DJ. Nicotine: from molecular mechanisms to behaviour. Curr Opin Pharmacol. 2005;5:53–9.

    Article  PubMed  CAS  Google Scholar 

  30. Changeux JP. Allosteric receptors: from electric organ to cognition. Annu Rev Pharmacol Toxicol. 2010;50:1–38.

    Article  PubMed  CAS  Google Scholar 

  31. Quik M, Perez XA, Bordia T. Nicotine as a potential neuroprotective agent for Parkinson’s disease. Mov Disord. 2012;27:947–57.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Buccafusco JJ, Beach JW, Terry AV. Desensitization of nicotinic acetylcholine receptors as a strategy for drug development. J Pharmacol Exp Ther. 2009;328:364–70.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Corringer PJ, Sallette J, Changeux JP. Nicotine enhances intracellular nicotinic receptor maturation: a novel mechanism of neural plasticity? J Physiol Paris. 2006;99:162–71.

    Article  PubMed  CAS  Google Scholar 

  34. Anderson SM, Brunzell DH. Low dose nicotine and antagonism of beta2 subunit containing nicotinic acetylcholine receptors have similar effects on affective behavior in mice. PLoS One. 2012;7:e48665.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Bordia T, McIntosh JM, Quik M. The nicotine-mediated decline in L-dopa-induced dyskinesias is associated with a decrease in striatal dopamine release. J Neurochem 2013;125:291–302. PMCID 377804.

    Google Scholar 

  36. Lai A, Parameswaran N, Khwaja M, Whiteaker P, Lindstrom JM, Fan H, et al. Long-term nicotine treatment decreases striatal alpha6* nicotinic acetylcholine receptor sites and function in mice. Mol Pharmacol. 2005;67:1639–47.

    Article  PubMed  CAS  Google Scholar 

  37. Carta M, Bezard E. Contribution of pre-synaptic mechanisms to levodopa-induced dyskinesia. Neuroscience. 2011;198:245–51.

    Article  PubMed  CAS  Google Scholar 

  38. Cenci MA. Dopamine dysregulation of movement control in LEVODOPA-induced dyskinesia. Trends Neurosci. 2007;30:236–43.

    Article  PubMed  CAS  Google Scholar 

  39. Fisone G, Bezard E. Molecular mechanisms of levodopa-induced dyskinesia. Int Rev Neurobiol. 2011;98:95–122.

    Article  PubMed  CAS  Google Scholar 

  40. Lindgren HS, Andersson DR, Lagerkvist S, Nissbrandt H, Cenci MA. LEVODOPA-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. 2010;112:1465–76.

    Article  PubMed  CAS  Google Scholar 

  41. Grady SR, Wageman CR, Patzlaff NE, Marks MJ. Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include alpha5 or alpha6 subunits and that mediate synaptosomal neurotransmitter release. Neuropharmacology. 2012;62:1935–43.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Domino EF, Ni L, Zhang H. Nicotine alone and in combination with levodopa methyl ester or the D(2) agonist N-0923 in MPTP-induced chronic hemiparkinsonian monkeys. Exp Neurol. 1999;158:414–21.

    Article  PubMed  CAS  Google Scholar 

  43. Meshul CK, Kamel D, Moore C, Kay TS, Krentz L. Nicotine alters striatal glutamate function and decreases the apomorphine-induced contralateral rotations in 6-OHDA-lesioned rats. Exp Neurol. 2002;175:257–74.

    Article  PubMed  CAS  Google Scholar 

  44. Schneider JS, Van Velson M, Menzaghi F, Lloyd GK. Effects of the nicotinic acetylcholine receptor agonist SIB-1508Y on object retrieval performance in MPTP-treated monkeys: comparison with levodopa treatment. Ann Neurol. 1998;43:311–7.

    Article  PubMed  CAS  Google Scholar 

  45. Marshall J, Schnieden H. Effect of adrenaline, noradrenaline, atropine, and nicotine on some types of human tremor. J Neurol Neurosurg Psychiatry. 1966;29:214–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Ishikawa A, Miyatake T. Effects of smoking in patients with early-onset Parkinson’s disease. J Neurol Sci. 1993;117:28–32.

    Article  PubMed  CAS  Google Scholar 

  47. Kelton MC, Kahn HJ, Conrath CL, Newhouse PA. The effects of nicotine on Parkinson’s disease. Brain Cogn. 2000;43:274–82.

    PubMed  CAS  Google Scholar 

  48. Mitsuoka T, Kaseda Y, Yamashita H, Kohriyama T, Kawakami H, Nakamura S, et al. Effects of nicotine chewing gum on UPDRS score and P300 in early-onset parkinsonism. Hiroshima J Med Sci. 2002;51:33–9.

    PubMed  CAS  Google Scholar 

  49. Villafane G, Cesaro P, Rialland A, Baloul S, Azimi S, Bourdet C, et al. Chronic high dose transdermal nicotine in Parkinson’s disease: an open trial. Eur J Neurol. 2007;14:1313–6.

    Article  PubMed  CAS  Google Scholar 

  50. Hanagasi HA, Lees A, Johnson JO, Singleton A, Emre M. Smoking-responsive juvenile-onset Parkinsonism. Mov Disord. 2007;22:115–9.

    Article  PubMed  Google Scholar 

  51. Lemay S, Chouinard S, Blanchet P, Masson H, Soland V, Beuter A, et al. Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:31–9.

    Article  PubMed  CAS  Google Scholar 

  52. Clemens P, Baron JA, Coffey D, Reeves A. The short-term effect of nicotine chewing gum in patients with Parkinson’s disease. Psychopharmacology (Berl). 1995;117:253–6.

    Article  CAS  Google Scholar 

  53. Ebersbach G, Stock M, Muller J, Wenning G, Wissel J, Poewe W. Worsening of motor performance in patients with Parkinson’s disease following transdermal nicotine administration. Mov Disord. 1999;14:1011–3.

    Article  PubMed  CAS  Google Scholar 

  54. Vieregge A, Sieberer M, Jacobs H, Hagenah JM, Vieregge P. Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study. Neurology. 2001;57:1032–5.

    Article  PubMed  CAS  Google Scholar 

  55. Shoulson I. Randomized placebo-controlled study of the nicotinic agonist SIB-1508Y in Parkinson disease. Neurology. 2006;66:408–10.

    Article  CAS  Google Scholar 

  56. Fagerstrom KO, Pomerleau O, Giordani B, Stelson F. Nicotine may relieve symptoms of Parkinson’s disease. Psychopharmacology (Berl). 1994;116:117–9.

    Article  CAS  Google Scholar 

  57. Kawamata J, Suzuki S, Shimohama S. alpha7 nicotinic acetylcholine receptor mediated neuroprotection in Parkinson’s disease. Curr Drug Targets. 2012;13:623–30.

    Article  PubMed  CAS  Google Scholar 

  58. Thiriez C, Villafane G, Grapin F, Fenelon G, Remy P, Cesaro P. Can nicotine be used medicinally in Parkinson’s disease? Expert Rev Clin Pharmacol. 2011;4:429–36.

    Article  PubMed  CAS  Google Scholar 

  59. Picciotto MR, Zoli M. Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Front Biosci. 2008;13:492–504.

    Article  PubMed  CAS  Google Scholar 

  60. Mudo G, Belluardo N, Mauro A, Fuxe K. Acute intermittent nicotine treatment induces fibroblast growth factor-2 in the subventricular zone of the adult rat brain and enhances neuronal precursor cell proliferation. Neuroscience. 2007;145:470–83.

    Article  PubMed  CAS  Google Scholar 

  61. Quik M, O’Neill M, Perez XA. Nicotine neuroprotection against nigrostriatal damage: importance of the animal model. Trends Pharmacol Sci. 2007;28:229–35.

    Article  PubMed  CAS  Google Scholar 

  62. Shimohama S. Nicotinic receptor-mediated neuroprotection in neurodegenerative disease models. Biol Pharm Bull. 2009;32:332–6.

    Article  PubMed  CAS  Google Scholar 

  63. Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol. 2012;72:893–901.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26 Suppl 1:S1–58.

    Article  PubMed  Google Scholar 

  65. Tanner CM. Advances in environmental epidemiology. Mov Disord. 2010;25 Suppl 1:S58–62.

    Article  PubMed  Google Scholar 

  66. Searles Nielsen S, Gallagher LG, Lundin JI, Longstreth Jr WT, Smith-Weller T, Franklin GM, et al. Environmental tobacco smoke and Parkinson’s disease. Mov Disord. 2012;27:293–6.

    Article  PubMed  Google Scholar 

  67. Elbaz A, Moisan F. Update in the epidemiology of Parkinson’s disease. Curr Opin Neurol. 2008;21:454–60.

    Article  PubMed  Google Scholar 

  68. Tanner CM, Goldman SM, Aston DA, Ottman R, Ellenberg J, Mayeux R, et al. Smoking and Parkinson’s disease in twins. Neurology. 2002;58:581–8.

    Article  PubMed  CAS  Google Scholar 

  69. Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50:279–90.

    PubMed  CAS  Google Scholar 

  70. Langmead CJ, Watson J, Reavill C. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther. 2008;117:232–43.

    Article  PubMed  CAS  Google Scholar 

  71. Yarnall A, Rochester L, Burn DJ. The interplay of cholinergic function, attention, and falls in Parkinson’s disease. Mov Disord. 2011;26:2496–503.

    Article  PubMed  Google Scholar 

  72. Gomez-Mancilla B, Bedard PJ. Effect of nondopaminergic drugs on Levodopa-induced dyskinesia in MPTP-treated monkeys. Clin Neuropharmacol. 1993;16:418–27.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We gratefully acknowledge support for NIH grants NS59910 and NS65851.

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Authors and Affiliations

  1. Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025, USA

    Maryka Quik, Tanuja Bordia, Danhui Zhang & Xiomara Perez

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  1. Maryka Quik
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  2. Tanuja Bordia
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  3. Danhui Zhang
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  4. Xiomara Perez
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Correspondence to Maryka Quik .

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Editors and Affiliations

  1. Toronto Western Hospital, Toronto, Ontario, Canada

    Susan H. Fox

  2. Toronto Western Hospital, Toronto, Ontario, Canada

    Jonathan M. Brotchie

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Quik, M., Bordia, T., Zhang, D., Perez, X. (2014). Involvement of the Cholinergic System in Levodopa-Induced Dyskinesia. In: Fox, S., Brotchie, J. (eds) Levodopa-Induced Dyskinesia in Parkinson's Disease. Springer, London. https://doi.org/10.1007/978-1-4471-6503-3_16

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  • DOI: https://doi.org/10.1007/978-1-4471-6503-3_16

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