In Vivo Neurochemical Analyses of Exogenously Administered L-DOPA: Implications for Treatment of Parkinson’s Disease

  • Elizabeth D. Abercrombie
  • Michael J. Zigmond
Part of the Advances in Behavioral Biology book series (ABBI, volume 39)


The fundamental therapeutic actions of L-DOPA in Parkinson’s disease are attributed to its ability to be taken up into the brain where it is converted to dopamine (DA) by the enzyme aromatic amino acid decarboxylase (AADC) (Birkmayer and Hornykiewicz, 1962; Lloyd et al., 1975; Melamed et al., 1984). Thus, it is believed that by replenishing the depleted stores of DA in the basal ganglia caused by the disease-related loss of DA neurons, the neurological deficits characteristic of Parkinson’s disease are ameliorated. However, although many insights regarding the therapeutic mechanism of action of L-DOPA in Parkinson’s disease have been gained, several important questions remain largely unresolved. Two of the issues which we have addressed in our laboratory are: 1) Is the release of DA formed from exogenous L-DOPA regulated in any way or does it merely reflect a non-specific spillover of DA from the site of formation? 2) Do the characteristics of the release of DA formed from exogenous L-DOPA in the intact striatum differ from those in the striatum lacking a normal dopaminergic innervation as in Parkinson’s disease?


Dopaminergic Neuron Intact Animal Uptake Site Dialysis Probe Dopaminergic Nerve Terminal 
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, E.D., Keefe, K.A., DiFrischia, D.S., and Zigmond, M.J., 1989a, Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex, J. Neurochem., 52: 1655.PubMedCrossRefGoogle Scholar
  2. Abercrombie, E.D., Keefe, K.A., and Zigmond, M.J., 1989b, Evidence that nerve terminal density is an important contributor to apparent differences in the activation of central dopamine systems, Behay. Pharmacol., 1 (Suppl.): 26.Google Scholar
  3. Abercrombie, E.D., Bonatz, A.E., and Zigmond, M.J., 1990, Effects of L-DOPA on extracellular dopamine in striatum of normal and 6hydroxydopamine-treated rats, Brain Res., in press.Google Scholar
  4. Barbeau, A., 1969, L-DOPA therapy in Parkinson’s disease: A critical review of nine years’ experience, Canad. Med. Assoc. J., 101: 59.Google Scholar
  5. Birkmayer, W., and Hornykiewicz, O., 1962, Der 1-dioxyphenylalanin (LDOPA-Effekt beim Parkinson-syndrom des menschen: Zur pathogenese und behadlung der Parkinson-akinese, Arch. Psychiat. Nervenkr., 203: 560.CrossRefGoogle Scholar
  6. Bunney, B.S., Aghajanian, G.K., and Roth, R.H., 1973, Comparison of effects of L-DOPA, amphetamine and apomorphine on firing rate of rat dopaminergic neuronesNature, 245: 123.Google Scholar
  7. Dexter, D.T., Carter, C.J., Wells, F.R., Javoy-Agid, F., Agid, Y., Lees, A., Jenner, P., and Marsden, C.D., 1989, Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease, J. Neurochem., 52: 381.PubMedCrossRefGoogle Scholar
  8. Ervin, G.N., Fink, J.S., Young, R.C., and Smith, G.P., 1977, Different behavioral responses to L-DOPA after anterolateral or posterolateral hypothalamic injections of 6-hydroxydopamine, Brain Res., 132: 507.PubMedCrossRefGoogle Scholar
  9. Globus, M., and Melamed, E., 1983, Combined administration of direct dopamine agonists and L-DOPA does not interfere with utilization of exogenous L-DOPA in rat corpus striatum, Proq. Neuropsychopharm. Biol. Psychiatry, 7: 211.CrossRefGoogle Scholar
  10. Graham, D.G., 1978, Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones, Mol. Pharmacol., 14: 633.Google Scholar
  11. Guttman, M., and Seeman, P., 1985, L-DOPA reverses the elevated density of D, dopamine receptors in Parkinson’s diseased striatum, J. Neural. Trans., 64: 93.CrossRefGoogle Scholar
  12. Hefti, F., Melamed, E., and Wurtman, R.J., 1981a, The site of dopamine formation in rat striatum after L-DOPA administration, J. Pharmacol. Exp. Ther., 217: 189.PubMedGoogle Scholar
  13. Hefti, F., Melamed, E., Bhawan, J., and Wurtman, R.J., 1981b, Long-term administration of L-DOPA does not damage dopaminergic neurons in the mouse, Neurology, 31: 1194.CrossRefGoogle Scholar
  14. Hollister, A.S., Breese, G.R., and Mueller, R.A., 1979, Role of monoamine neural systaems in L-dihydroxyphenylalanine-stimulated activity, J. Pharmacol. Exp. Ther., 208: 37.PubMedGoogle Scholar
  15. Imperato, A., and Di Chiara, G., 1984, Trans-striatal dialysis coupled to reverse-phase high performance liquid chromatography with electrochemical detection: A new method for the study of the in vivorelease of endogenous dopamine and metabolites, J. Neurosci., 4: 966.Google Scholar
  16. Langelier, P., Roberge, A.G., Boucher, R., and Poirier, L.J., 1973, Effects of chronically administered L-DOPA in normal and lesioned cats, J. Pharmacol. Exp. Ther., 187: 15.PubMedGoogle Scholar
  17. Lesser, R.P., Fahn, S., Snider, S.R., Cote, L.J., Isgreen, W.P., and Barrett, R.E., 1979, Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy, Neurology, 29: 1253.PubMedCrossRefGoogle Scholar
  18. Lloyd, K.G., Davidson, L., and Hornykiewicz, 0., 1975, The neurochemistry of Parkinson’s disease: Effect of L-DOPA therapy, J. Pharmacol. Exp. Ther., 195: 453.Google Scholar
  19. Melamed, E 1988, Mechanism of action of exogenous L-DOPA: Is it a physiological therapy for Parkinson’s disease?, in: “Parkinson’s Disease and Movement Disorders,” J. Jankovic and E. Tolosa, eds., Urban & Schwarzenberg, Baltimore-Munich.Google Scholar
  20. Melamed, E., and Dafni, N., 1982, Effect of electrical stimulation of nigrostriatal dopaminergic neurons on utilization of exogenous L-DOPA in rat corpus striatum. J. Pharm. Pharmacol., 34: 820.Google Scholar
  21. Melamed, E., Hefti, G., Bitton, V., and Globus, M., 1984, Suppression of L-dopa-induced circling in rats with nigral lesions by blockade of central dopa-decarboxylase: Implications for mechanism of action of L-dopa in Parkinsonism, Neurology, 34: 1566.PubMedCrossRefGoogle Scholar
  22. Melamed, E., Globus, M., Uzzan, A., and Rosenthal, J., 1985, Is dopamine formed from exogenous L-DOPA stored within vesicles in striatal dopaminergic nerve terminals: Implications for L-DOPA’s mechanism of action in Parkinson’s disease, Neurol., 35 (Suppl.): 118.Google Scholar
  23. Ng, K.Y., Chase, T.N., Colburn, R.W., and Kopin, I.J., 1972, L-DOPA in parkinsonism: A possible mechanism of action, Neurology, 22: 688.Google Scholar
  24. Ponzio, F., Achilli, G., Perego, C., Rinaldi, G., and Algeri, S., 1983, Does acute L-DOPA increase active release of dopamine from dopaminergic neurons?, Brain Res., 273: 45.PubMedCrossRefGoogle Scholar
  25. Porrino, L.J., Burns, R.S., Crane, A.M., Palombo, E., Kopin, I.J., and Sokoloff, L., 1987, Local cerebral metabolic effects of L-dopa therapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys, Proc. Nat. Acad. Sci. USA, 84: 5995.PubMedCrossRefGoogle Scholar
  26. Reches, A., Wagner, H.R., Jackson-Lewis, V., Yablonskaya-Alter, E., and Fahn, S., 1984, Chronic levodopa or pergolide administration induces down-regulation of dopamine receptors in denervated striatum, Neurology, 34: 1208.PubMedCrossRefGoogle Scholar
  27. Riederer, P., Sofic, E., Rausch, W.-D., Schmidt, B., Reynolds, G.P., Jellinger, K., and Youdim, M.B.H., 1989, Transition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains, J. Neurochem., 52: 515PubMedCrossRefGoogle Scholar
  28. Rinne, U.K., Sonninen, V., and Hyyppa, M., 1971, Effect of L-DOPA on brain monoamines and their metabolites in Parkinson’s disease, Life Sci., 10: 549.CrossRefGoogle Scholar
  29. Schoenfeld, R.I., and Uretsky, N.J., 1973, Enhancement by 6-hydroxydopamine of the effects of DOPA upon the motor activity of rats, J. Pharmacol. Exp. Ther., 186: 616.Google Scholar
  30. Spina, M.B., and Cohen, G., 1989, Dopamine turnover and glutathione oxidation: Implications for Parkinson’s disease, Proc. Nat. Acad. Sci. USA, 86: 1398.Google Scholar
  31. Steece-Collier, K., Collier, T.J., Sladek, C.D., and Sladek, J.R., 1989, Chronic L-DOPA treatment decreases the viability of grafted and cultured embryonic rat mesencephalic dopamine neurons, Soc. Neurosci. Abstr., 15: 1354.Google Scholar
  32. Trugman, J.M., and Wooten, G.F., 1986, The effects of L-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra, Brain Res., 379: 264.PubMedCrossRefGoogle Scholar
  33. Ungerstedt, U., 1984, Measurement of neurotransmitter release by intracranial dialysis, in: “Measurement of Neurotransmitter Release In Vivo,” C.A. Marsden, ed., Wiley, New York.Google Scholar
  34. Yahr, M.D., Wolf, A., Antunes, J.-L., Miyoshi, K., and Duffy, P., 1972, Autopsy findings in parkinsonism following treatment with levodopa, Neurology, 20 (Suppl.): 56.CrossRefGoogle Scholar
  35. Zigmond, M.J., and Stricker, E.M., 1980, Supersensitivity after intraventricular 6-hydroxydopamine: Relation to dopamine depletion, Experientia, 36: 436.PubMedCrossRefGoogle Scholar
  36. Zigmond, M.J., and Stricker, E.M., 1989, Animal models of Parkinsonism Using Selective Neurotoxins: Clinical and Basic Implications, Int. Rev. Neurobiol., 31: 1.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Elizabeth D. Abercrombie
    • 1
  • Michael J. Zigmond
    • 1
  1. 1.Depts. of Behavioral Neuroscience and PsychiatryUniversity of PittsburghPittsburghUSA

Personalised recommendations