Skip to main content
SpringerLink
Log in

Pathophysiology of L-Dopa-Induced Abnormal Involuntary Movements

  • Conference paper
Dyskinesia

Part of the book series: Psychopharmacology Supplementum ((PSYCHOPHARM,volume 2))

Abstract

Among the various deficiencies in neurotransmitters and neuropeptides in the brains of patients with Parkinson’s disease, the loss of dopamine (DA) is implicated in a major way in the occurrence of L-dopa-induced abnormal involuntary movements (AIMs). Whatever the clinical pattern, they are triggered by drugs which stimulate DA transmission and can be modified by DA agonists and antagonists. They occur when DOPA plasma concentrations, and thus central DA receptor stimulation, reach a critical level. They are observed in patients with severely damaged central DA neurons, but involvement of other neurotransmitter-containing cells cannot be excluded.

L-Dopa-induced AIMs have clinical and somatotopic characteristics, which vary from patient to patient. One might speculate that variable damage to DA neurons, associated or not with other neurotransmitter-containing cells in the affected brain structures, causes these differences in AIM patterns.

By analogy with behavioral experiments in animals, the hypersensitivity of DA receptors observed in the basal ganglia of parkinsonian patients post mortem might reasonably be considered to mediate L-dopa-induced AIMs. However, the role of various subtypes of DA receptors or of changes in DA metabolism in the cell bodies and dendrites (substantia nigra) or nerve terminals (striatolimbic areas) must also be considered. In brief, the features, topography, and timing of L-dopa-induced AIMs are dependent upon alterations of the functional expression of striatal DA output, which is not yet well understood.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Agid Y, Javoy F, Glowinski J (1973) Hyperactivity of remaining dopaminergic neurons after partial destruction of the nigrostriatal dopaminergic system in the rat. Nature 245: 150–151

    Article  CAS  Google Scholar 

  • Agid Y, Bonnet AM, Signoret JL, Lhermitte F (1979) Clinical, pharmacological and biochemical approach of “onset and end-of-dose” dyskinesias. In: Poirier LJ, Sourkes TL, Bedard PJ (eds) Advances in neurology, vol 24. Raven, New York, pp 401 –409

    Google Scholar 

  • Barbeau A (1976) Neurological and psychiatric side-effects of L-DOPA. Pharmacol Ther 1: 475–494

    Google Scholar 

  • Barbeau A, Mars H, Gillio-Joffroy L (1971) Adverse clinical side-effects of levodopa therapy. In: McDowell FH, Markham CH (eds) Parkinson’s disease. Davis, Philadelphia, pp 203–237

    Google Scholar 

  • Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations. J Neurol Sci 20: 415–455

    Article  PubMed  CAS  Google Scholar 

  • Blackwood W, Corsellis JAN (1976) Greenfields neuropathology, 3rd edn. Arnold, London

    Google Scholar 

  • Bokobza B, Ruberg M, Scatton B, Javoy-Agid F, Agid Y (1984) 3H-spiperone binding, dopamine and HVA concentrations in Parkinson’s disease and supranuclear palsy. Eur J Pharmacol 99: 167–175

    Article  PubMed  CAS  Google Scholar 

  • Cheramy A, Laviel V, Glowinski J (1981) Dendritic release of dopamine in the substantia nigra. Nature 289: 537

    Article  PubMed  CAS  Google Scholar 

  • Creese I, Burt DR, Snyder SH (1977) Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity. Science 197: 596–598

    Article  PubMed  CAS  Google Scholar 

  • Ericsson AD, Wertman BG, Duffy KM (1971) Reversal of the reserpine syndrome with L-DOPA metabolites in reserpinized rats. Neurology 21: 1023–1029

    PubMed  CAS  Google Scholar 

  • Escourolle R, De Recondo J, Gray F (1970) Etude anatomopathologique de syndromes parkinsoniens. In: De Ajuriaguerra J (ed) Monoamines, noyaux gris centraux et syndrome de Parkinson. Symposium Bel Air IV. Masson, Paris, pp 173–229

    Google Scholar 

  • Fahn S, David E (1972) Oro-faciaL-lingual dyskinesia due to anticholinergic medication. Trans Am Neurol Assoc 97: 277–279

    Google Scholar 

  • Farley IJ, Hornykiewicz O (1976) Noradrenaline in subcortical brain regions of patients with Parkinson’s disease and control subjects. In: Birkmayer W, Hornykiewicz O (eds) Advances in Parkinsonism. Roche, Basel, pp 178–185

    Google Scholar 

  • Feuerstein C, Serre F, Gavend M, Pellat J, Perret J, Tanche M (1977) Plasma O-Methyldopa in levodopa-induced dyskinesias: a bioclinical investigation. Acta Neurol Scand 56: 508–524

    Article  PubMed  CAS  Google Scholar 

  • Feuerstein C, Demenge P, Barrette G, Silice C, Guerin B, Mouchet P (1981) Long-term effects of nigrostriatal denervation on 3H-haloperidol binding. Eur J Pharmacol 76: 457–460

    Article  PubMed  CAS  Google Scholar 

  • Gershanik O, Heikkila RE, Duvoisin RC (1983) Behavioral correlations of dopamine receptors activation. Neurology 33: 1489–1492

    PubMed  CAS  Google Scholar 

  • Herrera-Marschitz M, Ungerstedt U (1984) Evidence that apomorphine and pergolide induce rotation in rats by different actions on D1 and D2 receptor sites. Eur J Pharmacol 98: 165–176

    Article  PubMed  CAS  Google Scholar 

  • Hornykiewicz O (1966) Dopamine (3-Hydroxytyramine) and brain function. Pharmacol Rev 18: 925–964

    PubMed  CAS  Google Scholar 

  • Javoy-Agid F, Agid Y (1980) Is the mesocortical dopaminergic system involved in Parkinson’s disease? Neurology 30: 1326–1330

    PubMed  CAS  Google Scholar 

  • Javoy-Agid F, Ploska A, Agid Y (1982a) Microtopography of TH, CAT, and GAD activity in the substantia nigra and ventral tegmental area of control and parkinsonian human brain. J Neurochem 37: 1218–1227

    Article  Google Scholar 

  • Javoy-Agid F, Ruberg M, Taquet H, Studler JM, Lloyd KG, Garbarg M, Llorens-Cortes C, Grouselle D, Agid Y (1982b) Biochemical neuroanatomy of the human substantia nigra (pas compacta) in normal and parkinsonian subject. In: Friedhoff AJ, Chase TN (eds) Gilles de la Tourette syndrome. Adv Neurol 35: 151–163

    Google Scholar 

  • Javoy-Agid F, Grouselle D, Tixier-Vidal A, Agid Y (1983) Thyrotropin releasing hormone in brain of patients with Parkinson’s disease. Neuropeptides 3: 405–410

    Article  PubMed  CAS  Google Scholar 

  • Javoy-Agid F, Ruberg M, Taquet H, Bokobza B, Agid Y, Gaspar P, Berger B, N’Guyen- Legros J, Alvarez C, Gray F, Hauw JJ, Scatton B, Rouquier L (1984a) Biochemical neuropathology of Parkinson disease. In: Hassler RG, Christ JF (eds) Parkinson-specific motor and mental disorders, role of the pallidum: pathophysiological, biochemical, and therapeutic aspects. Adv Neurol 40: 189–198

    Google Scholar 

  • Javoy-Agid F, Taquet H, Cesselin F, Epelbaum J, Grouselle D, Mauborgne A, Studler JM, AgidY (1984b) Neuropeptides in Parkinson’s disease. In: Usdin E (ed) Catecholamines: Neuropharmacology and central nervous system — Therapeutic aspects. Liss, New York, pp 35–42

    Google Scholar 

  • Javoy-Agid F, Ruberg M, Pique L, Bertagna X, Taquet H, Studler JM, Cesselin F, Epelbaum J, Agid Y (1984c) Biochemistry of the hypothalamus in Parkinson disease. Neurology 34: 672–676

    PubMed  CAS  Google Scholar 

  • Klawans HL, Weiner WJ (1974) Attempted use of haloperidol in the treatment of L-DOPA induced dyskinesias. J Neurol Neurosurg Psychiatry 37: 427–430

    Article  PubMed  Google Scholar 

  • Klawans HL, Crossett P, Dana N (1975) Effect of chronic amphetamine exposure on stereotyped behavior: implications for pathogenesis of L-DOPA-induced dyskinesias. In: Calne D, Chase TN, Barbeau A (eds) Dopaminergic mechanisms. Adv Neurol 9: 105–112

    Google Scholar 

  • Kuruma I, Bartholini G, Pletscher A (1970) L-DOPA induced accumulation of 3-O-methyL-DOPA in brain and heart. Eur J Pharmacol 10: 189–192

    Article  PubMed  CAS  Google Scholar 

  • Lee T, Seeman P, Rajput A, Farley IJ, Hornykiewicz O (1978) Receptor basis for dopaminergic supersensitivity in Parkinson’s disease. Nature 273: 59

    Article  PubMed  CAS  Google Scholar 

  • Lee T, Seeman P, Hornykiewicz O, Bilbao J, Tourtellotte WW (1981) Parkinson’s disease: low density and presynaptic location of D3 receptors. Brain Res 212: 494

    Article  PubMed  CAS  Google Scholar 

  • Lhermitte F, Agid Y, Signoret JL, Studier JM (1977a) Les dyskinesies de “début et fin de dose” provoquées par la L-DOPA. Rev Neurol 133, 5: 297–308

    PubMed  CAS  Google Scholar 

  • Lhermitte F, Agid Y, Feuerstein C, Serre F, Signoret JL, Studier JM, Bonnet AM (1977b) Mouvements anormaux provoquées par la L-DOPA dans la maladie de Parkinson: corrélation avec les concentrations plasmiques de DOPA et de O-méthy L-DOPA. Rev Neurol 133: 445–454

    PubMed  CAS  Google Scholar 

  • Lhermitte F, Signoret JL, Agid Y (1977c) Etude des effets d’une molécule originale le Tiapride, dans le traitement des mouvements anormaux d’origine extra-pyramidale. Sem Hop Paris 53: 9–15

    Google Scholar 

  • Lhermitte F, Agid Y, Signoret JL (1978) Onset and end-of-dose levodopa-induced dyskinesias, possible treatment by increasing the daily doses of levodopa. Arch Neurol 35: 261–263

    PubMed  CAS  Google Scholar 

  • Marsden CD, Parkes JD, Quinn N (1982) Fluctuations of disability in Parkinson’s disease — clinical aspects. In: Marsden CD, Fahn S (eds) Movement disorder. Butterworth Scientific, London, pp 96–122

    Google Scholar 

  • Mauborgne A, Javoy-Agid F, Legrand JC, AgidY, Cesselin F (1983) Decrease of substance P-like immunoreactivity in the substantia nigra and pallidum of parkinsonian brains. Brain Res 268: 167–170

    Article  PubMed  CAS  Google Scholar 

  • Mena I, Court J, Fuenzalida S, Papavasiliou PS, Cotzias GC (1970) Modification of chronic manganese poisoning treatment with L-DOPA or 5-OH-tryptophan N Engl J Med 282, 1: 5–9

    Article  PubMed  CAS  Google Scholar 

  • Mones RJ, Elizan TS, Seigel G (1971) Analysis of L-DOPA induced dyskinesias in 51 patients with parkinsonism. J Neurol Neurosurg Psychiatry 34: 668–673

    Article  PubMed  CAS  Google Scholar 

  • Muenter MD, Tyce GM (1971) L-DOPA therapy of Parkinson’s disease: plasma L-DOPA concentration, therapeutic response and side effects. Mayo Clin Proc 46: 231–239

    PubMed  CAS  Google Scholar 

  • Muenter MD, Sharpless NS, Tyce GM (1972) Plasma 3-O-methyL-DOPA in L-DOPA therapy in Parkinson’s disease. Mayo Clin Proc 47: 389–395

    PubMed  CAS  Google Scholar 

  • Muenter MD, Sharpless NS, Tyce GM, Darley FL (1977) Patterns of dystonia (“I-D-I” and “D-I-D”) in response to L-DOPA therapy for Parkinson’s disease. Mayo Clin Proc 52: 163–174

    PubMed  CAS  Google Scholar 

  • Nagatsu T, Kanamori T, Kato T, Iikuza R, Narabayashi H (1978) Dopamine stimulated adenylate cyclase activity in the human brain: changes in Parkinsonism. Biochem Med 19: 360–365

    Article  PubMed  CAS  Google Scholar 

  • Ohye C, Bouchard R, Boucher R, Poirier LJ (1970) Spontaneous activity of the putamen after chronic interruption of the dopaminergic pathway: effect of L-DOPA. J Pharm Exp Ther 175: 700–708

    CAS  Google Scholar 

  • Peaston MJT, Bianchine JR (1970) Metabolic studies and clinical observations during L-DOPA treatment of Parkinson’s disease. Br Med J 1, 5693: 400–403

    Article  PubMed  CAS  Google Scholar 

  • Poirier LJ, Sourkes TL, Bouvier G, Boucher R, Carabin S (1966) Striatal amines, experimental tremor and the effect of harmaline in the monkey. Brain 89: 37–52

    Article  PubMed  CAS  Google Scholar 

  • Quik M, Spokes EG, McKay AVP, Bannister R (1979) Alterations in 3H-spiperone binding in human caudate nucleus, substantia nigra and frontal cortex in Shy-Drager syndrome and Parkinson’s disease. J Neurol Sci 43: 429

    Article  PubMed  CAS  Google Scholar 

  • Reches A, Fahn S (1981) O-methyldopa interferes with striatal utilization of levodopa. Ann Neurol 10: 94–95

    Google Scholar 

  • Reisine TD, Fields JZ, Stern LZ, Johnson PC, Bird ED, Spokes E, Schreiner PS, Enna SJ (1977) Neurotransmitter receptor alterations in Parkinson’s disease. Life Sci 21: 335

    Article  PubMed  CAS  Google Scholar 

  • Riederer P, Ransch WD, Birkmayer W, Jellinger K, Danielczyk W (1978) Dopamine sensitive adenylate cyclase activity in the caudate nucleus and metabolic encephalopathies. J Neural Transm [Suppl 14]: 153

    Google Scholar 

  • Rinne UK, Koskinen V, Lonnberg P (1980) Neurotransmitter receptors in the parkinsonian brain. In: Rinne UK, Klinger M, Stamm M (eds) Parkinson’s disease. Current Progress, Problems and Management. Elsevier, Amsterdam, pp 93

    Google Scholar 

  • Rinvik E, Grofova I, Ottersen OP (1976) Demonstration of nigrotectal and nigroreticular projections in the cat by axonal transport of proteins. Brain Res 112: 388–394

    Article  PubMed  CAS  Google Scholar 

  • Rivera-Calimlin L, Tandron D, Anderson F, Joynt R (1977) The clinical picture and plasma levodopa metabolite profile of parkinsonism non responders. Treatment with levodopa and decarboxylase inhibitor. Arch Neurol 34: 228–232

    Google Scholar 

  • Sassin JF, Taub S, Weitzman ED (1972) Hyperkinesia and changes in behavior produced in normal monkeys by L-DOPA. Neurology 22: 1122–1125

    PubMed  CAS  Google Scholar 

  • Scatton B, Javoy-Agid F, Agid Y (1983) Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res 275: 321–328

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (1980) Brain dopamine receptors. Pharm Rev 3: 229–313

    Google Scholar 

  • Shibuya M (1979) Dopamine sensitive adenylate cyclase activity in the striatum of Parkinson’s disease. J Neurol Transm 44: 287

    Article  CAS  Google Scholar 

  • Sigwald J, Raymondeaud C (1970) Les mouvements anormaux observés au cours du traitement de la maladie de Parkinson par la L-DOPA. Rev Neurol 122, 2: 103–112

    PubMed  CAS  Google Scholar 

  • Taquet H, Javoy-Agid F, Hamon M, Legrand JC, Agid Y, Cesselin F (1983) Parkinson’s disease affects differently Met5 and Leu5-enkephalin in the human brain. Brain Res 280: 379–382

    Article  PubMed  CAS  Google Scholar 

  • Tarsy D, Parkes JD, Marsden CD (1975) Metoclopramide and pimozide in Parkinson’s disease and levodopa-induced dyskinesias. J Neurol Neurosurg Psychiatry 38: 331–335

    Article  PubMed  CAS  Google Scholar 

  • Tolosa ES, Martin WE, Cohen HP (1975) Dyskinesias during levodopa therapy. Lancet 1: 1381–1382

    Article  PubMed  CAS  Google Scholar 

  • Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced-de-generation of the nigrostriatal dopamine system. Acta Physiol Scand [Suppl] 367: 69–93

    CAS  Google Scholar 

  • Wade LA, Katzman R (1975) 3-O-methyldopa uptake and inhibition of L-DOPA at the blood brain barrier. Life Sci 17: 131–136

    Article  PubMed  CAS  Google Scholar 

  • Yahr MD (1970) Abnormal involuntary movements induced by dopa: clinical aspects. In: Barbeau A, McDowell FH (eds) L-DOPA and parkinsonism. Davis, Philadelphia, pp 101–108

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoire de Médecine Expérimentale, CHU Pitié-Salpêtrière, and Clinique de Neurologie et Neuropsychologie, Hôpital de la Salpêtrière, Boulevard de l’Hôpital, F-75635, Paris Cedex 13, France

    F. Javoy-Agid

Authors
  1. Y. Agid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A.-M. Bonnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Ruberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Javoy-Agid
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Medical Research, Psychiatry and Neurology Services at the Veterans Administration Medical Center, USA

    Daniel E. Casey MD (Clinical Investigator, Associate Professor, Collaborative Scientist) (Clinical Investigator, Associate Professor, Collaborative Scientist)

  2. Departments of Psychiatry and Neurology at the Oregon Health Sciences University, 97207, Portland, OR, USA

    Daniel E. Casey MD (Clinical Investigator, Associate Professor, Collaborative Scientist) (Clinical Investigator, Associate Professor, Collaborative Scientist)

  3. Oregon Regional Primate Research Center, 97006, Beaverton, OR, USA

    Daniel E. Casey MD (Clinical Investigator, Associate Professor, Collaborative Scientist) (Clinical Investigator, Associate Professor, Collaborative Scientist)

  4. Intramural Research Program, National Institute of Neurological and Communicative Disorders and Stroke, Department of Health and Human Services, National Institute of Health, 20205, Bethesda, MD, USA

    Thomas N. Chase MD (Director) (Director)

  5. H. Lundbeck A/S, Ottiliavej 7-9, DK-2500, Copenhagen-Valby, Denmark

    Anne Vibeke Christensen MSc Pharm, DSc (Vice-President, Director of Research) (Vice-President, Director of Research)

  6. Department AEH, Sct. Hans Mental Hospital, DK-4000, Roskilde, Denmark

    Jes Gerlach MD

Rights and permissions

Reprints and permissions

Copyright information

© 1985 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Agid, Y., Bonnet, AM., Ruberg, M., Javoy-Agid, F. (1985). Pathophysiology of L-Dopa-Induced Abnormal Involuntary Movements. In: Casey, D.E., Chase, T.N., Christensen, A.V., Gerlach, J. (eds) Dyskinesia. Psychopharmacology Supplementum, vol 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-70140-5_19

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-70140-5_19

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-70142-9

  • Online ISBN: 978-3-642-70140-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation