Recent Advances in the Biochemical Pharmacology of Extrapyramidal Movement Disorders

  • Harold L. Klawans
  • Christopher Goetz
  • Paul A. Nausieda
  • William J. Weiner
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 90)


The biochemical pharmacology of parkinsonism and choreatic dis orders has been reviewed in relationship to recent observations in the synaptic pharmacology of dopaminergic systems. Despite the fact that parkinsonism is usually due to a failure of presynaptic dopamine input into the striatum, an identical clinical syndrome can result from postsynaptic striatal dysfunction. Although clinically identical, these two states differ both biochemically and pharmacologically. Presynaptic parkinsonism is associated with decreased dopamine turnover in the brain and responds to levodopa. Neither of these facts applies to postsynaptic parkinsonism

Denervation hypersensitivity has been proposed as a mechanism in the production of levodopa-induced dyskinesias and neurolepticinduced tardive dyskinesias. The role of chronic dopamine agonism in the former suggests that denervation hypersensitivity is not the only factor and raises the question that the treatment of parkinsonism with such agonists may inevitably be associated with dyskinesias and psychosis

Recent theories of the biochemical pharmacology of extrapyramidal movement disorders are largely derived from three separate sets of hypotheses:
  1. 1)

    Dopamine and acetylcholine have antagonistic effects on striatal neurons and that the normal function of these neurons depends upon a balance of the influences of these two neurotransmitters.

  2. 2)

    A shift of this balance such that there is a decrease in dopamine activity results in the signs and symptoms of parkinsonism. In most, if not all, of these patients this decrease is felt to come about as a result of decreased dopamine input (i.e., presynaptic dysfunction).

  3. 3)

    A shift of this balance such that there is a relative in crease in dopaminergic activity results in choreatic movement disorders. This increase in dopaminergic activity is felt to be due to dysfunction of the striatal neurons (postsynaptic dysfunction). This is felt to be related to primary neuronal disease in Huntington’s chorea and to denervation hypersensitivity in tardive dyskinesias and levodopa-induced dyskinesias.

These basic concepts are based on a wide diversity of clinical and preclinical observations which have been reviewed extensively (üornykiewiczy 1966, Klawans, 1968, Klawans et al., 1970, Klawans, 1973). Rather than review these data once again, this review will focus on selected recent observations which serve to qualify and redefine these basic premises. We will focus on three particular issues:
  1. 1)

    The occurrence of parkinsonism as a result of striatal cell dysfunction, i.e., postsynaptic parkinsonism.

  2. 2)

    The role of chronic dopaminergic agonism in the pathogenesis of levodopa-induced hypersensitivity, i.e., agonist-induced hypersensitivity.

  3. 3)

    Further observation on the development of denervation hypersensitivity within the central nervous system.



Tardive Dyskinesia Stereotyped Behavior Levodopa Therapy Chronic Levodopa Choreic Movement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aminoff, M.F., Wilcox, C.S., Woakes, M.M. and Kremer, M. (1973). Levodopa therapy for parkinsonism in the Shy-Drager syndrome. J. Neurol. Neurosurg. Psychiatry 36, 350–353.CrossRefGoogle Scholar
  2. Anden, N.E. (1970). Pharmacological and anatomical implications of induced abnormal movements with L-dopa. In L-Dopa and Park insonism (Barbeau, A. and McDowell, F.H., Eds), pp. 132–143. F.A. Davis, Philadelphia.Google Scholar
  3. Andrews, J.M., Terry R.D. and Spataro, J. (1970). Striatonigral degeneration. Arch. Neurol. 23 ,319–327.CrossRefGoogle Scholar
  4. Barbeau, A. (1969). L-dopa and juvenile Huntington’s disease. Lancet 2 ,1066.CrossRefGoogle Scholar
  5. Barbeau, A., Marsh, H. and Gillo-Joffroy, L. (1971). Adverse clinical side effects of L-dopa therapy. In Recent Advances in Park inson’s Disease (McDowell, F.A. and Markham, C.H., Eds.), pp. 204–237. F.A. Davis, Philadelphia.Google Scholar
  6. Bertler, A., Jeppson, P.G., Nordgren, L., et al. (1971). Serial determinations of homovanillic acid in the cerebrospinal fluid of parkinson patients treated with L-dopa. Acta Neurol. Scand. 47 ,393–402.CrossRefGoogle Scholar
  7. Bird, M.T. and Paulson, G.W. (1970). Early onset rigid Huntingtons chorea. Neurology (Minneap.) 20 ,400.CrossRefGoogle Scholar
  8. Carlsson, A. (1970). Biochemical implications of dopa-induced actions on the central nervous system, with particular reference to abnormal movements. In L-Dopa and Parkinsonism (Barbeau, A. and McDowell, F.H., Eds.), pp. 205–213. F.A. Davis, Philadelphia.Google Scholar
  9. Chase, T.N. and Ng, L.K.Y. (1972). Central monoamine metabolism in Parkinson’s disease. Arch. Neurol. 27 ,486–491.CrossRefGoogle Scholar
  10. Costall, B. and Naylor, R.J. (1973). On the mode of action of apomorphine. Eur. J. Pharmacol. 21 ,350–361.CrossRefGoogle Scholar
  11. Ellinwood, E.H. (1967). Amphetamine psychosis. I. Description of the individuals and process. J. Nerv. Ment. Dis. 144 ,273–283.CrossRefGoogle Scholar
  12. Ernst, A.M. (1967). Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats. Psychopharmacologia (Bert.) 10, 316–323.CrossRefGoogle Scholar
  13. Fahn, S. and Breenberg, J. (1972). Striatonigral degeneration. Trans. Am. Neurol. Assoc. 97, 275–277.Google Scholar
  14. Faurbye, A. (1970). The structural and biochemical basis of movement disorders in the treatment with neuroleptic drugs in extrapyramidal diseases. Comp. Psychiatry 11 ,205–224.CrossRefGoogle Scholar
  15. Fjalland, B. and Moller-Nielsen, I. (1974). Enhancement of methyl- phenidate-induced stereotypies by repeated administration of neuroleptics. Psychopharmacologia (Berl.) 34 ,105–109.CrossRefGoogle Scholar
  16. Gianutsos, G., Drawbaugh, R.B., Hynes, M.D. and Lal, H. (1974). Behavioral evidence for dopamine supersensitivity after chronic haloperidol. Life Sci. 14 ,887–898.CrossRefGoogle Scholar
  17. Godwin-Austen, R.B., Kantamarreni, B.D. and Curzon, G. (1971). Comparison of benefit from L-dopa in parkinsonism with increase of amine metabolites in the CSF. J. Neurosurg. Psychiatry 34 ,219–223.CrossRefGoogle Scholar
  18. Goetz, C. and Klawans, H.L. (1974). Studies on the interaction of reserpine, d-amphetamine, apomorphine, and 5-hydroxytryptophan. Acta Pharmacol. Toxicol. 34.,119–L30.Google Scholar
  19. Greenfield, J.G. and Bosanquet, F.D. (1953). The brain stem lesion in parkinsonism. J. Neurol. Neurosurg. Psychiatry 16 ,213–226.CrossRefGoogle Scholar
  20. Gumpert, J., Sharpe, D. and Curzon, G. (1973). Amine metabolites in the cerebrospinal fluid in Parkinson’s disease and the response to levodopa. J. Neurol. Sci. 19 ,1–12.CrossRefGoogle Scholar
  21. Hornykiewicz, O. (1966). Dopamine (3-hydroxytyramine) and brain function. Pharmacol. Rev. 18 ,925–964.PubMedGoogle Scholar
  22. Izumi, K., Inoue, N., Shirabe, T., Miyazaki, T. and Kuroiwa, Y. (1971). Failed levodopa therapy in striatonigral degeneration. Lancet 1 ,1355.CrossRefGoogle Scholar
  23. Jequier, E. and Dufresne, J.J. (1972). Biochemical investigations in patients with Parkinson’s disease treated with L-dopa. Neurology (Minneap.) 22 ,15–21.CrossRefGoogle Scholar
  24. Jonas, W. and Scheel-Kruger, J. (1969). Amphetamine-induced stereotyped behavior correlates with the accumulation of O-methy- dopamine. Arch. Int. Pharmacody. 177 ,379–386.Google Scholar
  25. Klawans, H.L. (1968). The pharmacology of parkinsonism. Bis. Nerv. Syst. 29 ,805–816.Google Scholar
  26. Klawans, H.L. (1973). The Pharmacology of Extrapyramidal Movement Disorders. S. Karger, Basel.Google Scholar
  27. Klawans, H.L. (1975). Amine precursors in neurologic disorders and the psychoses. In Biology of Major Psychoses (Freedman, D.X., Ed.), pp. 259–272. Raven Press, New York.Google Scholar
  28. Klawans, H., Itaki, M.M. and Sheuher, D. (1970). Theoretical of the use L-dopa in parkinsonism. Acta Neur. Scand. 46 ,409–441.CrossRefGoogle Scholar
  29. Klawans, H.L. and Margolin, D.I. (1975). Amphetamine-induced dopa- minergic hypersensitivity in guinea pigs. Arch. Gen. Psychiatry 32 ,725–732.CrossRefGoogle Scholar
  30. Klawans, H.L. and Rubovits, R. (1972). An experimental model of tardive dyskinesia. J. Neural Transm. 33 ,235–246.CrossRefGoogle Scholar
  31. Klawans, H.L. and Rubovits, R. (1975). The pharmacology of tardive dyskinesia and some animal models. In Proceedings of the IX Confress of the Collegium Internationale Neuropsychopharma cologicum (Boissier, J.R., Hippius, H. and Pichot, P., Eds.), pp. 58–67. Excerpta Medica, Amsterdam.Google Scholar
  32. Klawans, H.L., Ilahi, M.M. and Ringel, S.P. (1971). Toward an under standing of the pathophysiology of Huntingtons chorea. Confin. Neurol. 33 ,297–303.CrossRefGoogle Scholar
  33. Klawans, H.L., Goetz, C., Westheimer, R. and Weiner, W.J. (1973a). 5-Hydroxytryptophan-induced behavior in intact guinea pigs. Res. Common. Chem, Pathol. Pharmacol. 5 ,555–559.Google Scholar
  34. Klawans, H.L., Goetz, C. and Weiner, W.J. (1973b). 5-Hydroxytryptophan-induced myoclonus in guinea pigs and the possible role of serotonin in infantile myoclonus. Neurology (Minneap.) 23 ,1234–1240).CrossRefGoogle Scholar
  35. Klawans, H.L., Crosset, P. and Dana, N. (1975a). Effect of chronic amphetamine exposure on stereotyped behavior: Implications for pathogenesis of L-dopa-induced dyskinesias. In Advances in Neurology, vol. 9 (Calne, D.B., Chase, T.N. and Barbeau, A., Eds.), pp. 105–112. Raven Press, New York.Google Scholar
  36. Klawans, H.L., D’Amico, D.J. and Patel, B.C. (1975b). Behavioral supersensitivity to 5-hydroxytryptophan induced by chronic methysergide pretreatment. Psychopharmacologia (Berl.) 44 ,297–300.CrossRefGoogle Scholar
  37. Klawans, H.L., Lupton, M.D. and Simon, L. (1976a). Calcification of the basal ganglia as a cause of levodopa resistant parkinsonism. Neurology (Minneap.) 26 ,221–225.CrossRefGoogle Scholar
  38. Klawans, H.L., D’Amico, D.J., Nausieda, P.A. and Weiner, W.J. (1976). The specificity of neuroleptic- and methysergide-induced behavioral hypersensitivity. Presented at the American Academy of Neurology Annual Meeting, April, 1976, Toronto, Canada.Google Scholar
  39. Kramer, J., Fischman, V.S. and Littlefield, D.S. (1967). Amphetamine abuse — pattern and effects of high doses taken intravenously. J.A.M.A. 201 ,305–309.CrossRefGoogle Scholar
  40. Low, P.A., Allsop, J.L. and Halmayi, G.M. (1974). The rigid form (Westphal variant) treated with levodopa. Med. J. Aust. 1 ,393–394.PubMedGoogle Scholar
  41. Nausieda, P.A., Crosset, P. and Klawans, H.L. (in press): Effect of chronic dopaminergic agonism on subsequent response to amphetamine and apomorphine. Encephale.Google Scholar
  42. Ohye, C., Bouchard, R., Boucher, R. and Poirier, L.J. (1970). Spontaneous activity of the putamen after chronic interruption of the dopaminergic pathway. J. Pharmacol. Exp. Ther. 175 ,700–708.Google Scholar
  43. Rajput, A., Kazi, D.A. and Rozdilsky, B. (1972). Striatonigral degeneration: Response to levodopa therapy. J. Neurol. Sci. 16 ,331–341.CrossRefGoogle Scholar
  44. Rinne, U.K., Sonninen, V. and Surtola, T. (1973). Acid monoamine metabolites in the cerebrospinal fluid of parkinson patients treated with levodopa alone or combined with a decarboxylase inhibitor. Eur. Neurol. 9 ,349–362.CrossRefGoogle Scholar
  45. Rubovits, R. and Klawans, H.L. (1972). Implications of amphetamineinduced stereotyped behavior as a model for tardive dyskinesia. Arch. Gen. Psychiatry 27 ,502–507.CrossRefGoogle Scholar
  46. Rylander, G. (1972). Psychoses and the punding and choreiform syndromes in addiction to central stimulant drugs. Psychiatr. Neurol. Neurochir. 75 ,203–212.PubMedGoogle Scholar
  47. Sharpe, J.A., Newcastle, N.B., Lloyd, K.G., et al. (1973). Stria-tonigral degeneration. J. Neurol. Sci. 20 ,275–286.CrossRefGoogle Scholar
  48. Tarsy, D. and Baldessarini, R.J. (1974). Behavioral supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines. Neuropharmacology 13 ,927–940.CrossRefGoogle Scholar
  49. Tarsy, D. and Baldessarini, R.J. (1976). The tardive dyskinesia syndrome. In Clinical Neuropharmacology (Klawans, H.L., Ed.), pp. 29–61. Raven Press, New York.Google Scholar
  50. Trotter, J.L. (1973). Striatonigral degeneration, Alzheimer’s disease, and inflammatory changes. Neurolofy (Minneap.) 23 ,1211–1216.CrossRefGoogle Scholar
  51. Ungerstedt, U. (1971). Postsynaptic supersensitivity after 6-hydroxy dopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol. Scand. (Suppl.) 367 ,69–93.CrossRefGoogle Scholar
  52. Weiner, W.J. and Klawans, H.L. (1973). Failure of cerebrospinal fluid homovanillic acid to predict levodopa response in Parkin son’s disease. J. Neurol. Neurosurg. Psychiatry 36 ,747–752.CrossRefGoogle Scholar
  53. Weiner, W.J., Harrison, W.H. and Klawans, H.L. (1969). L-dopa and cerebrospinal fluid homovanillic acid in parkinsonism. Life Sci. 8 ,971–976.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Harold L. Klawans
    • 1
    • 2
  • Christopher Goetz
    • 1
  • Paul A. Nausieda
    • 1
    • 2
  • William J. Weiner
    • 1
    • 2
  1. 1.Division of NeurologyMichael Reese Hospital and Medical CenterChicagoUSA
  2. 2.Department of Medicine (Neurology)University of Chicago Pritzker School of MedicineChicagoUSA

Personalised recommendations