CNS Compensation to Dopamine Neuron Loss in Parkinson’s Disease

  • Kenneth G. Lloyd
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


Postmortem studies in brains from parkinsonian patients consis tently reveal a minimum loss of 75% of the nigrostriatal dopamine neurons. This indicates that over a prolonged period, before Parkinson’s disease is clinically evident, there is a physiological compensation for the slow loss of dopamine neurons (i.e. compensated stage of Parkinson’s disease). Only when the dopamine neuron loss is sufficiently severe (greater than 75% of nigrostriatal dopamine neurons) does the disease become clinically evident (decompensated state). Postmortem examination of Parkinson’s disease brains and study of animal models indicate that the following mechanisms may contribute to this CNS compensation:

1) A decrease in striatal cholinergic activity, in an attempt to maintain a critical DA:ACh balance; and 2) A decrease in activity of GABA neurons in the striatum and substantia nigra, resulting in an increased firing rate of nigral dopamine cells. These mechanisms allow the brain to readjust to the initial dopamine cell loss in Parkinson’s disease.


Substantia Nigra Dopamine Neuron Gaba Neuron Tyrosine Hydroxylase Activity Choline Acetyl Transferase 
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.


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  1. Agid, Y., Javoy, F. and Glowinski, J. (1973). Hyperactivity of re maining dopaminergic neurons after partial destruction of the nigrostriatal dopaminergic system in the rat. Nature, New Bio. 245 ,150–151.CrossRefGoogle Scholar
  2. Agid, Y., Guyenet, P., Glowinski, J. Beaujouan, J.C. and Javoy, F. (1975). Inhibitory influence of the nigrostriatal dopamine system on the striatal cholinergic neurons in the rat. Brain Research 86` ,488–492.Google Scholar
  3. Asper, H., Baggiolini, M., Burki, H.R., Lauener, H. Ruch, W. and Stille, G. (1973). Tolerance phenomena with neuroleptiGS catalepsy, apormophine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol. Enrop. J. Pharmacol. 22 ,287–294.CrossRefGoogle Scholar
  4. Axelrod, J. (1971). Noradrenaline: Fate and control of its biosynthesis. Science 173 ,598–606.PubMedCrossRefGoogle Scholar
  5. Bartholini, G., Stadler, H., Gadea-Cirea, M. and Lloyd, K.G. (1975). The effect of antipsychotic drugs on the release of neurotransmitter in various brain areas. In Antipsychotic Drugs - Pharma codynamics and Pharmacokinetics (Sedvall, G., Ed.) pp. 105–116. Pergamon Press, New York.Google Scholar
  6. Bernheimer, H., Birkmayer, W. and Hornykiewicz, O. (1961). Verteilung des 5-Hydroxytryptamin (Serotonin) im Gehirn des Menschen und sein Verhalten bei Patienten mit Parkinson-Syndrom. Klin. Wech. 39 ,1056–1059.CrossRefGoogle Scholar
  7. Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K. and Seitelberger, F. (1973). Brain dopamine and the syndromes of Parkinson and Huntington. J. Neurol. Sci. 20 ,415–455.PubMedCrossRefGoogle Scholar
  8. Crossman, A.R., Walker, R.J. and Woodruff, G.N. (1973). Picrotoxin antagonism of γ-aminobutyric acid inhibitory responses and synaptic inhibition in the rat substantia nigra. Brit. J. Pharmacol. 49 ,696–698.CrossRefGoogle Scholar
  9. Dray, A. and Straughan, D.W. (1976). Synaptic mechanisms in the substantia nigra. J. Pharm. Pharmacol. 28 ,400–405.PubMedCrossRefGoogle Scholar
  10. Duvoisin, R.C. (1967). Cholinergic-Anticholinergic antagonism in parkinsonism. Arch. Neurol. 17 ,124–136.PubMedCrossRefGoogle Scholar
  11. Feltz, P. (1971). γ-Aminobutyric acid and a caudate-nigral inhibition. Can. J. Physiol. Pharmacol. 49 ,113–115.CrossRefGoogle Scholar
  12. Fonnum, F., Grofova, I., Rinvik, E., Storm-Mathisen, J. and Walberg, F. (1974). Origin and distribution of glutamate decarboxylase in substantia nigra of the cat. Brain Research 71 ,77–92.PubMedCrossRefGoogle Scholar
  13. Greenblatt, D.J. and Shader, R.I. (1973). Anticholinergics. New Engl. J. Med. 288 ,1215–1219.PubMedCrossRefGoogle Scholar
  14. Hattori, T., McGeer, P.L., Fibiger, H.C. and McGeer, E.G. (1973). On the source of GABA-containing terminals in the substantia nigra: Electron microscopic, autoradeographic and biochemical studies. Brain Research 54 ,103–114.Google Scholar
  15. Hockman, C.H., Lloyd, K.G., Farley, I.J. and Hornykiewicz, O. (1971). Experimental midbrain lesions: Neurochemical comparison between the animal model and Parkinson’s Disease. Brain Research 35 ,613–618.PubMedCrossRefGoogle Scholar
  16. Hollister, L.E. (1972). Mental disorders-antipsychotic and antimanic drugs. New Engl. J. Med. 286 ,984–987.PubMedCrossRefGoogle Scholar
  17. Hornykiewicz, O. (1966). Dopamine (3-Hydroxytyramine) and brain function. Pharmacol. Revs. 18 ,925–964.Google Scholar
  18. Hornykiewicz, O. (1975). Parkinsonism induced by dopaminergic anta gonists. In Advances in Neurology, Vol. 9 (Calne, D.B. and Barbeau, A., Eds.) pp. 155–164, Raven Press, New York.Google Scholar
  19. Kim, J.S. and Hassler, R. (1975). Effects of acute haloperidol on the gamma-aminobutyric acid system in rat striatum and substantia nigra. Brain Research 88 ,150–153.PubMedCrossRefGoogle Scholar
  20. Kim. J.S., Bak, I.J., Hassler, R. and Okada, Y. (1971). Role of gamma-aminobutyric acid (GABA) in the extrapyramidal motor system. Exp. Brain Research 14 ,95–104.Google Scholar
  21. Klett, C.J. and Caffey, E. (1972). Evaluating the long-term need for antiparkinson drugs by chronic schizophenics. Arch. Gen. Psychiat. 26 ,374–379.PubMedCrossRefGoogle Scholar
  22. Lloyd, K.G. (1972). Biogenic amines and related enzymes in the human and animal brain. Ph.D. Thesis, University of Toronto.Google Scholar
  23. Lloyd, K.G. (1976). Observations concerning neurotransmitter interaction in schizophrenia. In Cholinergic-monoaminergic inter action in the brain (Butcher, L.L., Ed.) In Press, Academic Press, New York.Google Scholar
  24. Lloyd, K.G. and Hornykiewicz, O. (1973). L-Glutamic acid Decarboxylase in Parkinson’s disease: Effect of L-dopa therapy. Nature 243 ,521–523.PubMedCrossRefGoogle Scholar
  25. Lloyd, K.G. and Hornykiewicz, O. (1974). Dopamine and Other monoamines in the basal ganglia: Relation to brain dysfunction. In Frontiers in Neurology and Neuroscience Research, 1974. (Seeman, P. and Brown, G.M., Eds.) pp. 26–35. University of Toronto Press, Toronto.Google Scholar
  26. Lloyd, K.G., Davidson, L. and Hornykiewicz, O. (1975). The neurochemistry of Parkinson’s disease: Effect of L-dopa therapy. J. Pharmacol. Exp. Therap. 195 ,453–464.Google Scholar
  27. Lloyd, K.G., Möhler, H., Bartholini, G. and Hornykiewicz, O. (1976). Pathological alterations in glutamic acid decarboxylase activity in Parkinson’s disease. In Fifth International Symposium on Parkinson’s Disease (Birkmayer, W. and Hornykiewicz, O., Eds.) In Press, Editiones Roche, Basel.Google Scholar
  28. Lloyd, K.G., Möhler, H., Hertz, Ph. and Bartholini, G. (1975). Distribution of choline acetyltransferase and glutamic acid decarboxylase within the substantia nigra and in other brain regions from control and parkinsonian patients, J. Neurochem. 25 ,789–795.PubMedCrossRefGoogle Scholar
  29. Lloyd, K.G., Shemen, L. and Hornykiewicz, O. (1976). Distribution of high affinity Sodium-independent 3H-gamma-aminobutyric acid (3H-GABA Binding) in the human brain: Alterations in Parkinson’s disease. Brain Research. In Press.Google Scholar
  30. Lloyd, K.G., Shibuya, M., Davidson, L. and Hornykiewicz, O. (1976). Chronic neuroleptic therapy: Tolerance and GABA Systems. In Symposium on Non-Striatal Dopamine (Costa E. and Gessa, G.L., Eds.) In Press, Raven Press, New York.Google Scholar
  31. Lloyd, K.G., Stadler, H. and Bartholini, G. (1973). Dopamine and acetylcholine neurons in striatal and limbic structures: Effect of neuroleptic drugs. In Frontiers in Catecholamine Research (Usdin, E. and Snyder, S., Eds.) pp. 777–779. Pergamon Press, Oxford.Google Scholar
  32. McGeer, P.L., McGeer, E.G., Wada, J.A. and Jung, E. (1971). Effects of globus pallidus lesions and Parkinson’s disease on brain glutamic acid decarboxylase. Brain Research 32 ,425–431.PubMedCrossRefGoogle Scholar
  33. McGeer, P.L., McGeer, E.G. and Fibiger, H.C. (1973). Glutamic-acid decarboxylase and choline acetylase in Huntington’s Chorea and Parkinson’s disease. Lancet ii ,623–624.CrossRefGoogle Scholar
  34. McGeer, P.L., Grewaal, D.S. and McGeer, E.G. (1976). Effect on extrapyramidal GABA levels of drugs which influence dopamine and acetylcholine metabolism. In Fifth International Symposium on Parkinson’s Disease (Birkmayer, W. and Hornykiewicz, O., Eds.) In Press, Editiones Roche, Basel.Google Scholar
  35. Perez de la Mora, M., Fuxe, K. Hokfelt, T. and Ljungdahl, A. (1975). Effect of apomorphine on the GABA Turnover in the dopamine cell group rich area of the mesencephalon: Evidence for the involvement of an inhibitory GAB Aergic feedback control of the ascending dopaminergic neurons. Neurosci. Letts. 1 ,109–114.Google Scholar
  36. Precht, W. and Yoshida, M. (1971). Blockage of caudate-evoked inhibition of neurons in the substantia nigra by picratoxin. Brain Research 32 ,229–233.PubMedCrossRefGoogle Scholar
  37. Sethy, V.H. and Van Woert, M.H. (1974a). Regulation of striatal acetylcholine concentrations by dopamine receptors. Nature 251 ,529–530.PubMedCrossRefGoogle Scholar
  38. Sethy, V.H. and Van Woert, M.H. (1974b). Modification of striatal acetylcholine concentrations by dopamine receptor agonists and antagonists. Res. Comm. Chem. Fathol. Pharmacol. 8 ,13–28.Google Scholar
  39. Simpson, G.M. (1974). Clozapine: A new antipsychotic drug. Curr. Therap. Research. 16 ,679–686.Google Scholar
  40. Trabucchi, M. Cheney, D., Racagni, G. and Costa, E. (1974). Involvement of brain cholinergic mechanisms in the action of chlorpromazine. Nature 249 ,664–666.PubMedCrossRefGoogle Scholar
  41. Trabucchi, M., Cheney, D.L., Racagni, G. and Costa, E. (1975). In vivo inhibition of striatal acetylcholine turnover by L-dopa, apomorphine and (+)-amphetamine. Brain Research 85 ,130–134.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Kenneth G. Lloyd
    • 1
    • 2
  1. 1.Departments of Psychiatry and PharmacologyUniversity of TorontoTorontoCanada
  2. 2.Department of PsychopharmacologyClarke Institute of PsychiatryTorontoCanada

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