Intrapallidal dopamine restores motor deficits induced by 6-hydroxydopamine in the rat

  • A. Galvan
  • B. Floran
  • D. Erlij
  • J. Aceves


To explore whether dopamine deficits in the globus pallidus have a role in generating the motor symptoms of Parkinson’s disease, we examined the effects of selective intrapallidal administration of dopamine or its antagonists in rats unilaterally lesioned with 6-hydroxydopamine into the medial forebrain bundle. Either the turning behavior induced by apomorphine or the deficit in the performance of a skilled forelimb-reaching task was used as assay for drug action. Microinjection of either the D2 receptor antagonist, sulpiride, or the Dl receptor antagonist, SCH-23390, into the dopamine-denervated pallidum significantly reduced apomorphine induced turning. In animals trained to perform a skilled forelimb-reaching task, 6-OHDA lesions caused a marked motor deficit in the contralateral forelimb. Intrapallidal dopamine applied either intermittently or continuously, restored up to 50% of the motor performance. Continuous application promoted a motor recovery that outlasted dopamine administration. These results show that lack of dopamine in the GP plays an important role in generating the motor symptoms caused by lesion of dopaminergic pathways. Moreover, motor recovery was produced by selectively injecting dopamine into the globus pallidus.


Dopamine dopamine Dl receptors dopamine D2 receptors GABA globus pallidus Parkinson’s disease turning behavior staircase test 


  1. Abrous DN, Shaltot AR, Torres EM, Dunnett SB (1993) Dopamine-rich grafts in the neostriatum and/or nucleus accumbens: effects on drug-induced behaviors and skilled paw-reaching. Neuroscience 53: 187–197PubMedCrossRefGoogle Scholar
  2. Aceves J, Cuello AC (1981) Dopamine release induced by electrical stimulation of microdissected caudate-putamen and substantia nigra of the rat brain. Neuroscience 6: 2069–2075PubMedCrossRefGoogle Scholar
  3. Aceves J, Floran B, Martinez-Fong D, Sierra A, Hernandez S, Mariscal S (1991) L-dopa stimulates the release of [3H] gamma-aminobutyric acid in the basal ganglia of 6-hydroxydopamine lesioned rats. Neurosci Lett 121: 223–226PubMedCrossRefGoogle Scholar
  4. Ariano MA, Wang J, Noblett KL, Larson ER, Sibley DR (1997) Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera. Brain Res 752: 26–34PubMedCrossRefGoogle Scholar
  5. Barone P, Tucci I, Parashos SA, Chase TN (1987) D-1 dopamine receptor changes after striatal quinolinic acid lesion. Eur J Pharmacol 138: 141–145PubMedCrossRefGoogle Scholar
  6. Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC (1991) Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 564: 203–219PubMedCrossRefGoogle Scholar
  7. Boyson SJ, McGonigle P, Molinoff PB (1986) Quantitative autoradiographic localization of the Dl and D2 subtypes of dopamine receptors in the rat brain. J Neurosci 5: 3177–3188Google Scholar
  8. Cossette M, Levesque M, Parent A (1999) Extrastriatal dopaminergic innervation of human basal ganglia. Neurosci Res 34: 51–54PubMedCrossRefGoogle Scholar
  9. Costall B, Naylor RJ, Olley JE (1972a) Stereotypic and anticataleptic activities of amphetamine after intracerebral injections. Eur J Pharmacol 18: 83–94PubMedCrossRefGoogle Scholar
  10. Costall B, Naylor RJ, Olley JE (1972b) Catalepsy and circling behaviour after intracerebral injections of neuroleptic, cholinergic and anticholinergic agents into the caudate-putamen, globus pallidus and substantia nigra of rat brain. Neuropharmacology 11: 645–663PubMedCrossRefGoogle Scholar
  11. Dubois A, Savasta M, Curet O, Scatton B (1986) Autoradiographic distribution of the Dl agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience 19: 125–137PubMedCrossRefGoogle Scholar
  12. EmgÁrd-Mattson M, Karlsson J, Nakao N, Brundin P (1997) Addition of lateral ganglionic eminence to rat mesencephalic grafts affects fiber outgrowth but does not enhance function. Cell Transplant 6: 277–286PubMedCrossRefGoogle Scholar
  13. Floran B, Aceves J, Sierra A, Martinez-Fong D (1990) Activation of D1 dopamine receptors stimulates the release of GABA in the basal ganglia of the rat. Neurosci Lett 116: 136–140PubMedCrossRefGoogle Scholar
  14. Floran B, Floran L, Sierra A, Aceves J (1997) D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus. Neurosci Lett 237: 1–4PubMedCrossRefGoogle Scholar
  15. Flores G, Liang JJ, Sierra A, Martinez-Fong D, Quirion R, Aceves J, Srivastava LK (1999) Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography. Neuroscience 91: 549–556PubMedCrossRefGoogle Scholar
  16. Fox CA, Mansour A, Thompson RC, Bunzow JR, Civelli O, Watson SJ Jr (1993) The distribution of dopamine D2 receptor heteronuclear RNA (hnRNA) in the rat brain. J Chem Neuroanat 6: 363–373PubMedCrossRefGoogle Scholar
  17. Fremeau RT Jr, Duncan GE, Fornaretto MG, Dearry A, Gingrich JA, Breese GR, Caron MG (1991) Localization of Dl dopamine receptor mRNA in brain supports a role in cognitive, affective, and neuroendocrine aspects of dopaminergic neurotransmission. Proc Natl Acad Sci USA 88: 3772–3776PubMedCrossRefGoogle Scholar
  18. Gandia JA, De Las Heras S, Garcia M, Gimenez-Amaya JM (1993) Afferent projections to the reticular thalamic nucleus from the globus pallidus and the substantia nigra in the rat. Brain Res Bull 32: 351–358PubMedCrossRefGoogle Scholar
  19. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380: 252–255PubMedCrossRefGoogle Scholar
  20. Hargraves R, Freed WJ (1987) Chronic intrastriatal dopamine infusions in rats with unilateral lesions of the substantia nigra. Life Sci 40: 959–966PubMedCrossRefGoogle Scholar
  21. Hauber W, Lutz S (1999) Dopamine D1 or D2 receptor blockade in the globus pallidus produces akinesia in the rat. Behav Brain Res 106: 143–150PubMedCrossRefGoogle Scholar
  22. Hazrati LN, Parent A (1991) Projection from the external pallidum to the reticular thalamic nucleus in the squirrel monkey. Brain Res 550: 142–146PubMedCrossRefGoogle Scholar
  23. Hedreen JC (1999) Tyrosine hydroxylase-immunoreactive elements in the human globus pallidus and subthalamic nucleus. J Comp Neurol 409: 400–410PubMedCrossRefGoogle Scholar
  24. Huang Q, Zhou D, Chase K, Gusella JF, Aronin N, DiFiglia M (1992) Immunohis-tochemical localization of the Dl dopamine receptor in rat brain reveals its axonal transport, pre- and postsynaptic localization, and prevalence in the basal ganglia, limbic system, and thalamic reticular nucleus. Proc Natl Acad Sci USA 89: 11988–11992PubMedCrossRefGoogle Scholar
  25. Kasamatsu T, Itakura T, Jonsson G (1981) Intracortical spread of exogenous catecholamines: effective concentration for modifying cortical plasticity. J Pharmacol Exp Ther 217: 841–850PubMedGoogle Scholar
  26. Kroin JS, Kao LC, Zhang TJ, Penn RD, Klawans HL, Carvey PM (1991) Dopamine distribution and behavioral alterations resulting from dopamine infusion into the brain of the lesioned rat. J Neurosurg 74: 105–111PubMedCrossRefGoogle Scholar
  27. Lazarov NE, Schmidt U, Wanner I, Pilgrim C (1998) Mapping of Dl dopamine receptor mRNA by non-radioactive in situ hybridization. Histochem Cell Biol 109: 271–279PubMedCrossRefGoogle Scholar
  28. Levey AT, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA, Price DL, Maggio R, Brann MR, Ciliax BJ (1993) Localization of Dl and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci USA 90: 8861–8865PubMedCrossRefGoogle Scholar
  29. Limón ID, Martínez-Fong D, Nuñez A, Rosales MG, Aceves J (1998) Differential modulation of GABA and glutamate release by D2 and Dl dopamine receptors in the globus pallidus. Soc Neurosci Abstr 24: 6474Google Scholar
  30. Lindvall O, Björklund A (1979) Dopaminergic innervation of the globus pallidus by collaterals from the nigrostriatal pathway. Brain Res 172: 169–173PubMedCrossRefGoogle Scholar
  31. Mansour A, Meador-Woodruff JH, Bunzow JR, Civelli O, Akil H, Watson SJ (1990) Localization of dopamine D2 receptor mRNA and Dl and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor autoradiographic analysis. J Neurosci 10: 2587–2600PubMedGoogle Scholar
  32. Mansour A, Meador-Woodruff JH, Zhou QY, Civelli O, Akil H, Watson SJ (1991) A comparison of Dl receptor binding and mRNA in rat brain using receptor autoradiographic and in situ hybridization techniques. Neuroscience 45: 359–371PubMedCrossRefGoogle Scholar
  33. Mayer GS, Shoup RE (1983) Simultaneous multiple electrode chromatographic-electrochemical assay for catecholamines. J Chromatrogr 255: 533–544CrossRefGoogle Scholar
  34. Montoya CP, Campbell-Hope LJ, Pemberton KD, Dunnett SB (1991) The “staircase test”: a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Methods 36: 219–228PubMedCrossRefGoogle Scholar
  35. Moriizumi T, Hattori T (1992) Separate neuronal populations of the rat globus pallidus projecting to the subthalamic nucleus, auditory cortex and pedunculopontine tegmental area. Neuroscience 46: 701–710PubMedCrossRefGoogle Scholar
  36. Najlerahim A, Barton AJ, Harrison PJ, Heffernan J, Pearson RC (1989) Messenger RNA encoding the D2 dopaminergic receptor detected by in situ hybridization histochemistry in rat brain. FEBS Lett 255: 335–339PubMedCrossRefGoogle Scholar
  37. Nikkhah G, Duan WM, Knappe U, Jödicke A, Björklund A (1993) Restoration of complex sensorimotor behavior and skilled forelimb use by a modified nigral cell suspension transplantation approach in the rat Parkinson model. Neuroscience 56: 33–43PubMedCrossRefGoogle Scholar
  38. Nikkhah G, Cunningham MG, McKay R, Bjorklund A (1995) Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery. J Neurosci 15: 3562–3570PubMedGoogle Scholar
  39. Olsson M, Nikkhah G, Bentlage C, Bjorklund A (1995) Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15: 3863–3875PubMedGoogle Scholar
  40. Parent A, Smith Y (1987) Differential dopaminergic innervation of the two pallidal segments in the squirrel monkey (Saimiri sciureus). Brain Res 426: 397–400PubMedCrossRefGoogle Scholar
  41. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San DiegoGoogle Scholar
  42. Pifl C, Schingnitz G, Hornykiewicz O (1992) Striatal and non-striatal neurotransmitter changes in MPTP-parkinsonism in rhesus monkey: the symptomatic versus the asymptomatic condition. Neurochem Int 20 [Suppl]: 295S-297SPubMedCrossRefGoogle Scholar
  43. Richfield EK, Young AB, Penney JB (1987) Comparative distribution of dopamine D-l and D-2 receptors in the basal ganglia of turtles, pigeons, rats, cats, and monkeys. J Comp Neurol 262: 446–463PubMedCrossRefGoogle Scholar
  44. Segovia J, Vergara P, Brenner M (1998) Astrocyte-specific expression of tyrosine hydroxylase after intracerebral gene transfer induces behavioral recovery in experimental Parkinsonism. Gene Ther 5: 1650–1655PubMedCrossRefGoogle Scholar
  45. Sendelbeck SL, Urquhart J (1985) Spatial distribution of dopamine, methotrexate and antipyrine during continuous intracerebral microperfusion. Brain Res 328: 251–258PubMedCrossRefGoogle Scholar
  46. Shammah-Lagnado SJ, Alheid GF, Heimer L (1996) Efferent connections of the caudal part of the globus pallidus in the rat. J Comp Neurol 376: 489–507PubMedCrossRefGoogle Scholar
  47. Smith Y, Bevan MD, Shink E, Bolam JP (1998) Microcircuitry of the direct and indirect pathways of the basal ganglia. Neuroscience 86: 353–387PubMedCrossRefGoogle Scholar
  48. Weiner DM, Levey AI, Sunahara RK, Niznik HB, ODowd BF, Seeman P, Brann MR (1991) Dl and D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci USA 88: 1859–1863PubMedCrossRefGoogle Scholar
  49. Whishaw IQ, Pellis SM (1990) The structure of skilled forelimb reaching in the rate: a proximally driven movement with a single distal rotatory component. Behav Brain Res 41: 49–59PubMedCrossRefGoogle Scholar
  50. Winkler C, Bentlage C, Nikkhah G, Samii M, Bjorklund A (1999) Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants. Exp Neurol 155: 165–186PubMedCrossRefGoogle Scholar
  51. Yung KK, Bolam JP, Smith AD, Hersch SM, Ciliax BJ, Levey AI (1995) Immuno-cytochemical localization of Dl and D2 dopamine receptors in the basal ganglia of the rat: light and electron microscopy. Neuroscience 65: 709–730PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • A. Galvan
    • 1
  • B. Floran
    • 1
  • D. Erlij
    • 2
  • J. Aceves
    • 1
    • 3
  1. 1.Departamento de FisiologíaBiofísica y Neurociencias, Centro de Investigatión y de Estudios Avanzados del Instituto Politécnico Nacional, México D. F.México
  2. 2.Department of PhysiologySUNY Downstate Medical CenterBrooklynU.S.A.
  3. 3.Department of PhysiologyCINVESTAV-IPNMéxico D.F.México

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