Partial damage to nigrostriatal bundle: compensatory changes and the action of L-DOPA

  • M. J. Zigmond
  • E. D. Abercrombie
  • E. M. Stricker
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 29)


Parkinson’s disease is associated with degeneration of the nigrostriatal bundle. However, the neurological symptoms that accompany this disease do not emerge until the degenerative process is almost complete. Early studies with animals models suggested that the extensive preclinical phase of Parkinsonism was due in part to the development of a compensatory hyper-activity within remaining dopamine-containing neurons. Other studies suggested that systemic administration of L-DOPA could reduce the neurological symptoms once they emerged by further increasing the availability of dopamine in striatum. Subsequent work has supported both hypothesis.


Substantia Nigra Homovanillic Acid Striatal Cell Striatal Slice Central Noradrenergic Neuron 
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. Abercrombie ED, Zigmond MJ (1989) Partial injury to central noradrenergic neurons: reduction of tissue norepinephrine content is greater than reduction of extracellular norepinephrine measured by microdialysis. J Neurosci 9: 4062–4067.PubMedGoogle Scholar
  2. Acheson AL, Zigmond MJ (1981) Short and long term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons. J. Neurosci 1: 493–504.PubMedGoogle Scholar
  3. Agid Y, Javoy F, Glowinski J (1973) Hyperactivity of remaining dopaminergic neurons after partial destruction of the nigro-striatal dopaminergic system in the rat. Nature NewBiol 245: 150–151.CrossRefGoogle Scholar
  4. Barbeau A, Murphy GF, Sourkes TL (1962) Les catecholamines dans la maladie de Parkinson. In: de Ajuriaguerra J (ed) Monoamines et système nerveux central Georg & Cie, Geneve, pp 247-262.Google Scholar
  5. Bartholini G, Blum JE, Pletscher A (1969) DOPA-induced locomotor stimulation after inhibition of extracerebral decarboxylase. J Pharm Pharmacol 21: 297–301.PubMedCrossRefGoogle Scholar
  6. 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: 415–55.PubMedCrossRefGoogle Scholar
  7. Bertler A, Falck B, Owman C, Rosengren E (1966) The localization of nonaminergic blood-brain barrier mechanisms. Pharmacol Rev 18: 369–385.PubMedGoogle Scholar
  8. Birkmayer W, Horny kiewicz O (1962) Der 1-dioxyphenylalanin (= L-dopa)-Effekt beim Parkinson-Syndrom des Menschen: Zur Pathogenese und Behandlung der Parkinsonakinese. Arch Psychiatry 203: 560–574.CrossRefGoogle Scholar
  9. Bonatz AE, Morris HJ, Zigmond MJ, Abercrombie ED (1989) L-DOPA produces higher levels of extracellular dopamine in dopamine depleted striata. Soc Neurosci Abstr 15: 124.Google Scholar
  10. Burns R, Chiueh C, Markey S, Ebert M, Jacobowitz D, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc Natl.Acad Sci USA 80: 4546–4550.PubMedCrossRefGoogle Scholar
  11. Burns RS, Chiueh CC, Parisi J, Markey S, Kopin IJ (1986) Biochemical and pathological effects of MPTP: the rhesus monkey. In: Fahn S, Marsden CD, Jenner P, Teychenne P (eds) Recent developments in Parkinson’s disease. Raven Press, New York, pp 127–136.Google Scholar
  12. Carlsson A, Lindqvist M, Magnusson T (1957) 3,4-Dihydroxyphenylalanin and 5-hydroxytryptophan as reserpine antagonists. Nature 180: 1200.PubMedCrossRefGoogle Scholar
  13. Chiodo LA, Acheson AL, Zigmond MJ, Strieker EM (1983) Subtotal destruction of central noradrenergic projections increases the firing rate of locus coeruleus cells. Brain Res. 264: 123–126.PubMedCrossRefGoogle Scholar
  14. Chiueh CC, Burns RS, Markey SP, Jacobowitz DM, Kopin IJ (1985) Primate model of parkinsonism: selective lesion of nigrostriatal neurons by l-methyl-4-phenyl-l,2,3,6tetrahydropyridine produces an extrapyramidal syndrome in rhesus monkeys. Life Sei. 36: 213–218.CrossRefGoogle Scholar
  15. Cotzias GC, Van Woert MH, Schiffer LM (1967) Aromatic amino acids and modification of parkinsonism. N Engl J Med 276: 374–379.PubMedCrossRefGoogle Scholar
  16. Creese I, Snyder SH (1979) Nigrostriatal lesions enhance striatal 3H-spiroperiodol binding. Eur J Pharmacol 56: 277–281.PubMedCrossRefGoogle Scholar
  17. Cubeddu LX, Hoffmann IS, James MK (1983) Frequency-dependent effects of neuronal uptake inhibitors on the autoreceptor-mediated modulation of dopamine and acetylcholine release from the rabbit striatum. J Pharmacol Exp Ther 226: 88.PubMedGoogle Scholar
  18. Doucet G, Descarries L, Garcia S (1986) Quantification of the dopamine innervation in adult rat neostriatum. Neuroscience 19: 427–445.PubMedCrossRefGoogle Scholar
  19. Duvoisin RC, Heikkila RE, Nicklas WJ, Hess A (1986) Dopamine neurotoxicity of MPTP in the mouse: a murine model of parkinsonism. In: Fahn S, Marsden CD, Jenner P, Teychenne P (eds) Recent developments in Parkinson’s disease. Raven Press, New York, pp 147–154.Google Scholar
  20. Duvoisin RC, Mytilineou C (1972) Where is L-DOPA decarboxylated in the striatum after 6-hydroxydopamine nigrotomy? Brain Res 152: 369–373.CrossRefGoogle Scholar
  21. Edwards AV (1982) Adrenal catecholamine output in response to stimulation of the splanchnic nerve in bursts in the conscious calf. J Physiol 327: 409–419.PubMedGoogle Scholar
  22. Ehringer H, Hornykiewicz O (1960) Verteilung von Noradrenalin und Dopamin (3-hy-droxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Wien Klin Wschr 38: 1236–1239.CrossRefGoogle Scholar
  23. Gonon FG (1988) Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry. Neuroscience 24: 19–28.PubMedCrossRefGoogle Scholar
  24. Heffner TG, Zigmond MJ, Strieker EM (1977) Effects of dopaminergic agonists and antagonists on feeding in intact and 6-hydroxydopamine-treated rats. J Pharmacol Exp Ther 201: 386–399.PubMedGoogle Scholar
  25. Hefti F, Melamed E (1981) Dopamine release in rat striatum after administration of L-DOPA as studied with in vivo electrochemistry. Brain Res 225: 333–346.PubMedCrossRefGoogle Scholar
  26. Hefti F, Melamed E, Sahakian BJ, Wurtman RJ (1980a) Circling behavior in rats with partial, unilateral nigro-striatal lesions: effect of amphetamine, apomorphine, and DOPA. Pharm Biochem Behav 12: 185–188.CrossRefGoogle Scholar
  27. Hefti F, Melamed E, Wurtman RJ (1980 b) Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res 195: 123–137.PubMedCrossRefGoogle Scholar
  28. Hefti F, Melamed E, Wurtman RJ (1981) The site of dopamine formation in rat striatum after L-DOPA administration. J Pharmacol Exp Ther 217: 189–197.PubMedGoogle Scholar
  29. Hollerman JR, Berger TW, Grace AA (1986) Compensatory changes in the activity of nigral dopamine cells in respone to partial dopamine-depleting lesions. Soc Neurosci Abstr 12: 872.Google Scholar
  30. Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson’s disease. In: Yahr M, Bergman K (eds) Advances in neurology, vol 45. Raven Press, New York, pp 19–34.Google Scholar
  31. Javoy-Agid F, Ruberg M, Hirsch E, Cash R, Raisman R, Taquet H, Epelbaum J, Scatton B, Duyckaerts C, Agid Y (1986) Recent progress in the neurochemistry of Parkinson’s disease. In: Fahn S, Marsden CD, Jenner P, Teychenne P (eds) Recent developments in Parkinson’s disease. Raven Press, New York, pp 67–83.Google Scholar
  32. Keller RW Jr, Kuhr WG, Wightman RM, Zigmond MJ (1988) The effect of L-DOPA on in vivo dopamine release from nigrostriatal bundle neurons. Brain Res 447: 191–194.PubMedCrossRefGoogle Scholar
  33. Kelly RS, Wightman RM (1987) Detection of dopamine overflow and diffusion with voltammetry in slices of rat brain. Brain Res 423: 79–87.PubMedCrossRefGoogle Scholar
  34. Langlier P, Parent A, Poirier LJ (1972) Decarboxylase activity of the brain capillary wall and parenchyma in the rat, cat, and monkey. Brain Res 45: 622–629.CrossRefGoogle Scholar
  35. Langston JW (1985) MPTP neurotoxicity: an overview and characterization of phases of toxicity. Life Sci 36: 201–206.PubMedCrossRefGoogle Scholar
  36. Langston JW, Forno LS, Rebert CS, Irwin I (1984) l-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine causes selective damage to the zona compacta of the substantia nigra in the squirrel monkey. Brain Res 292: 390–394.PubMedCrossRefGoogle Scholar
  37. Ljungberg T, Ungerstedt U (1976) Reinstatement of eating by dopamine agonists in aphagic dopamine denervated rats. Physiol Behav 16: 277–283.PubMedCrossRefGoogle Scholar
  38. Lloyd KG, Davidson L, Hornykiewicz O (1975) The neurochemistry of Parkinson’s disease:effect of L-DOPA therapy. J Pharmacol Exp Ther 195: 453–464.PubMedGoogle Scholar
  39. Lundberg JM, Rudehill A, Sollevi A, Fried G, Wallin G (1990) Co-release of neuropeptide Y and noradrenaline from pig spleen in vivo: importance of subcellular storage, nerve impulse frequency and pattern, feedback regulation and resupply by axonal transport. Neuroscience 28: 475–486.CrossRefGoogle Scholar
  40. Lytle LD, Hurko O, Romero JA, Cottman K, Leehey D, Wurtman RJ (1972) The effects of 6-hydroxydopamine pretreatment on the accumulation of DOPA and dopamine in brain and peripheral organs following L-DOPA administration. J Neural Transm 33: 63–72.PubMedCrossRefGoogle Scholar
  41. MacKenzie RG, Stachowiak M, Zigmond MJ (1989) Dopaminergic inhibition of striatal acetylcholine release after 6-hydroxydopamine. Eur J Pharmacol 168: 43–52.PubMedCrossRefGoogle Scholar
  42. Melamed E, Hefti F, Wurtman RJ (1980) Nonaminergic striatal neurons convert exogenous L-DOPA to dopamine in parkinsonism. Ann Neurol 8: 558–563.PubMedCrossRefGoogle Scholar
  43. Ng KY, Chase TN, Colburn RW, Kopin IJ (1970) L-DOPA-induced release of cerebral monoamines. Science 170: 76–77.PubMedCrossRefGoogle Scholar
  44. Ng KY, Chase TN, Colburn RW, Kopin IJ (1972) L-DOPA in Parkinsonism: a possible mechanism of action. Neurology 22: 688–696.PubMedGoogle Scholar
  45. Orr WB, Gardiner TW, Strieker EM, Zigmond MJ, Berger TW (1986) Short-term effects of dopamine-depleting brain lesions on spontaneous activity of striatal neurons: relation to local striatal dopamine levels and behavior. Brain Res 376: 20–28.PubMedCrossRefGoogle Scholar
  46. Robinson TE, Whishaw IQ (1988) Normalization of extracellular dopamine in striatum following recovery from a partial 6-OHDA lesion of the substantia nigra: a micro-dialysis study in freely moving rats. Brain Res 450: 209–244.PubMedCrossRefGoogle Scholar
  47. Schoenfeld RI, Uretsky NJ (1973) Enhancement by 6-hydroxydopamine of the effects of dopa upon the motor activity of rats. J Pharmacol Exp Ther 186: 616–624.PubMedGoogle Scholar
  48. Schoenfeld RI, Zigmond MJ (1973) Behavioural pharmacology of 6-hydroxydopamine. In: Usdin E, Snyder SH (eds) Frontiers in catecholamine research. Pergamon Press, New York, pp 695–700.Google Scholar
  49. Schultz W, Ungerstedt U (1978) Short-term increase and long-term reversion of striatal cell activity after degeneration of the nigrostriatal dopamine system. Exp Brain Res 33: 159–171.PubMedCrossRefGoogle Scholar
  50. Sharman DF, Poirier LJ, Murphy GF, Sourkes TL (1967) Homovanillic acid and dihydroxyphenylacetic acid in the striatum of monkeys with brain lesions. Can J Physiol Pharmacol 45: 57–62.PubMedCrossRefGoogle Scholar
  51. Snyder AM, Strieker EM, Zigmond MJ (1985) Stress-induced neurological impairments in an animal model of parkinsonism. Ann Neurol 18: 544–551.PubMedCrossRefGoogle Scholar
  52. Snyder GL, Zigmond MJ (1990) The effects of L-DOPA on in vitro dopamine release from striatum. Brain Res 508: 181–187.PubMedCrossRefGoogle Scholar
  53. Snyder GL, Stachowiak MK, Keller RW Jr, Strieker EM, Zigmond MJ (1986) Release of endogenous DA and DOPAC from striatal slices after DA-depleting lesions: effects of stimulation frequency and DA synthesis inhibition. Soc Neurosci Abstr 12: 136.Google Scholar
  54. Sourkes TL (1961) Formation of dopamine in vivo: relation to the function of the basal ganglia. Rev Can Biol 20: 187–196.Google Scholar
  55. Sourkes TL, Poirier LJ (1966) Neurochemical bases of tremor and other disorders of movement. Can Med Assoc J 94: 53–60.PubMedGoogle Scholar
  56. Stachowiak MK, Keller RW Jr, Strieker EM, Zigmond MJ (1987) Increased dopamine efflux from striatal slices during development and after nigrostriatal bundle damage. J Neurosci 7: 1648–1654.PubMedGoogle Scholar
  57. Stadler H, Lloyd K, Gadea-Ciria M, Bartholini G (1973) Enhanced striatal acetylcholine release by chlorpromazine and its reversal by apomorphine. Brain Res 55: 476–480.PubMedCrossRefGoogle Scholar
  58. Strieker EM, Zigmond MJ (1974) Effects on homeostasis of intraventricular injection of 6-hydroxydopamine in rats. J Comp Physiol Psychol 86: 973–994.CrossRefGoogle Scholar
  59. Strieker EM, Zigmond MJ (1976) Recovery of function after damage to central catechol-amine-containing neurons: a neurochemical model for the lateral hypothalamic syndrome. In: Sprague J, Epstein AN (eds) Progress in psychobiology and physiological psychology, vol 6. Academic Press, New York, pp 121–188.Google Scholar
  60. Tyce GM, Rorie DK (1985) Effects of L-DOPA and L-tyrosine on release of free and conjugated dopamine, homovanillic acid and dihydroxyphenylacetic acid from slices of rat striatum. Life Sci 37: 2439–2448.PubMedCrossRefGoogle Scholar
  61. Ungerstedt U (1971) Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand [Suppl 367]: 95-122.Google Scholar
  62. Vizi ES, Harsing LG, Knoll J (1977) Presynaptic inhibition leading to disinhibition of acetylcholine release from interneurons of the caudate nucleus: effects of dopamine, beta-endorphin and D-Ala2-Pro-5-enkephalinamide. Neuroscience 2: 953–961.CrossRefGoogle Scholar
  63. Zhang WQ, Tilson HA, Nanry KP, Hudson PM, Hong JS, Stachowiak MK (1988) Increased dopamine release from striata of rats after unilateral nigrostriatal bundle damage. Brain Res 461: 335–342.PubMedCrossRefGoogle Scholar
  64. Zigmond MJ, Acheson AL, Stachowiak MK, Strieker EM (1984) Neurochemical compensation after nigrostriatal bundle injury in an animal model of preclinical Parkinsonism. Arch Neurol 41: 856–861.PubMedCrossRefGoogle Scholar
  65. Zigmond MJ, Strieker EM (1973) Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions. Science 182: 717–720.PubMedCrossRefGoogle Scholar
  66. Zigmond MJ, Strieker EM (1980) Supersensitivity after intraventricular 6-hydroxydopamine: relation to lesion dopamine depletion. Experientia 36: 436–438.PubMedCrossRefGoogle Scholar
  67. Zigmond MJ, Strieker EM (1989) Animal models of Parkinsonism using selective neuro-toxins: clinical and basic implications. In: Smythies JR, Bradley RJ (eds) International review of neurobiology, vol 31. Academic Press, New York, pp 1–79.Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • M. J. Zigmond
    • 1
    • 2
  • E. D. Abercrombie
    • 1
  • E. M. Stricker
    • 1
  1. 1.Departments of Behavioral Neuroscience and Psychiatry and Center for NeuroscienceUniversity of PittsburghPittsburghUSA
  2. 2.Department of Behavioral NeuroscienceUniversity of PittsburghPittsburghUSA

Personalised recommendations