Protection Against Nigrostriatal Dopamine Cell Death by Pedunculopontine Tegmental Nucleus Lesions

  • Masahiko Takada
  • Masaru Matsumura
  • Jun Kojima
  • Yoshio Yamaji
  • Masahiko Inase
  • Hironobu Tokuno
  • Atsushi Nambu
  • Hisamasa Imai
Part of the Advances in Behavioral Biology book series (ABBI, volume 52)


It is well known that the pathogenesis of Parkinson’s disease is striatal dopamine deficiency subsequent upon degeneration of neurons in the substantia nigra pars compacta (SNc, Albin et al., 1989; DeLong, 1990). Several lines of evidence indicate that the pedunculopontine tegmental nucleus (PPN) is a major origin of excitatory glutamatergic input to nigrostriatal dopamine neurons (Kojima et al., 1997; Scarnati and Florio, 1997; Bezard and Gross, 1998). Recently, the importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has been emphasized in the development of Parkinson’s disease (Greenamyre, 1993; Schmidt, 1995; Starr, 1995; Lange et al., 1997). Based on the previous idea that an excitatory mechanism mediated by glutamatergic neurotransmission is closely associated with the onset of neurodegenerative disorders (Choi, 1988; Olney, 1988, 1989; Klockgether and Turski, 1989), we tested the hypothesis that ablation of the glutamatergic input derived from the PPN might prevent nigrostriatal cell death and parkinsonian motor signs that could be induced by the dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).


Tyrosine Hydroxylase Substantia Nigra Kainic Acid Glutamatergic Input Pedunculopontine Nucleus 
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. Albin, R. L., Young, A. B., and Penney, J. B., 1989, The functional anatomy of basal ganglia disorders, Trends Neurosci. 12:366–375.PubMedCrossRefGoogle Scholar
  2. Aziz, T. Z., Peggs, D., Sambrook, M. A., and Crossman, A. R., 1991, Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate, Mov. Disord 6:288–292.PubMedCrossRefGoogle Scholar
  3. Bergman, H., Wichmann, T., and De Long, M. R., 1990, Reversal of experimental parkinsonism by lesions of the subthalamic nucleus, Science 249:1436–1438.PubMedCrossRefGoogle Scholar
  4. Bezard, E., and Gross, C. E., 1998, Compensatory mechanisms in experimental and human Parkinsonism: towards a dynamic approach, Prog. Neurobiol. 55:93–116.PubMedCrossRefGoogle Scholar
  5. Blaha, C. D., and Winn, P., 1993, Modulation of dopamine efflux in the striatum following cholinergic stimulation of the substantia nigra in intact and pedunculopontine tegmental nucleus-lesioned rats, J. Neurosci. 13:1035–1044.PubMedGoogle Scholar
  6. Bolam, J. P., Francis, C. M., and Henderson, Z., 1991, Cholinergic input to dopaminergic neurons in the substantia nigra: a double immunocytochemical study, Neuroscience 41:483–494.PubMedCrossRefGoogle Scholar
  7. Carlsson, M., and Carlsson, A., 1990, Interactions between glutamatergic and monoaminergic systems within the basal ganglia — implications for schizophrenia and Parkinson’s disease, Trends Neurosci. 13:272–276.PubMedCrossRefGoogle Scholar
  8. Chapman, C. A., Yeomans, J. S., Blaha, C. D., and Blackburn, J. R., 1997, Increased striatal dopamine efflux follows scopolamine administered systemically or to the tegmental pedunculopontine nucleus, Neuroscience 76:177–186.PubMedCrossRefGoogle Scholar
  9. Charara, A., Smith, Y., and Parent, A., 1996, Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vu/garis-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry, J. Comp. Neurol. 364:254–266.PubMedCrossRefGoogle Scholar
  10. Choi, D. W., 1988, Glutamate neurotoxicity and diseases of the nervous system, Neuron 1:623–634.PubMedCrossRefGoogle Scholar
  11. DeLong, M. R., 1990, Primate models of movement disorders of basal ganglia origin, Trends Neurosci. 13:281–285.PubMedCrossRefGoogle Scholar
  12. Di Chiara, G., Morelli, M., and Consolo, S., 1994, Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions, Trends Neurosci. 17:228–233.PubMedCrossRefGoogle Scholar
  13. Di Loreto, S., Florio, T., and Scarnati, E., 1992, Evidence that non-NMDA receptors are involved in the excitatory pathway from the pedunculopontine region to nigrostriatal dopaminergic neurons, Exp. Brain Res. 89:79–86.PubMedCrossRefGoogle Scholar
  14. Futami, T., Takakusaki, K., and Kitai, S. T., 1995, Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta, Neurosci. Res. 21:331–342.PubMedCrossRefGoogle Scholar
  15. Guridi, J., Luquin, M. R., Herrero, M. T., and Obeso, J. A., 1993, The subthalamic nucleus: a possible target for stereotaxic surgery in Parkinson’s disease, Mov. Dis. 8:421–429.CrossRefGoogle Scholar
  16. Greenamyre, J. T., 1993, Glutamate-dopamine interactions in the basal ganglia: relationship to Parkinson’s disease, J. Neural Transco. (Gen. Sect.) 91:255–269.CrossRefGoogle Scholar
  17. Herkenham, M., Little, M. D., Bankiewicz, K., Yang, S.-c., Markey, S. P., and Johannessen, J. N., 1991, Selective retention of MPP` within the monoaminergic systems of the primate brain following MPTP administration: an in vivo autoradiographie study, Neuroscience 40:133–158.PubMedCrossRefGoogle Scholar
  18. Hernández-López, S., Góngora-Alfaro, J. L., Martinez-Fong, D., and Aceves, J., 1992, A cholinergic input to the substantia nigra pars compacta increases striatal dopamine metabolism measured by in vivo voltammetry, Brain Res. 598:114–120.PubMedCrossRefGoogle Scholar
  19. Klockgether, T., and Turski, L., 1989, Excitatory amino acids and the basal ganglia: implications for the therapy of Parkinson’s disease, Trends Neurosci. 12:285–286.PubMedCrossRefGoogle Scholar
  20. Klockgether, T., Löschmann, P.-A., and Wúllner, U., 1994, New medical and surgical treatments for Parkinson’s disease, Curr. Opin. Neural. 7:346–352.CrossRefGoogle Scholar
  21. Kojima, J., Yamaji, Y., Matsumura, M., Nambu, A., Inase, M., Tokuno, H., Takada, M., and ‘mai, H., 1997, Excitotoxic lesions of the pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the monkey, Neurosci. Leu. 226:111–114.CrossRefGoogle Scholar
  22. Lange, K. W., Kornhuber, J., and Riederer, P.. 1997, Dopamine/glutamate interactions in Parkinson’s disease. Neurosci. Biobehay. Rev. 21:393–400.CrossRefGoogle Scholar
  23. Lavoie, B., and Parent, A., 1994a, Pedunculopontine nucleus in the squirrel monkey: distribution of cholinergic and monoaminergic neurons in the mesopontine tegmentum with evidence for the presence of glutamate in cholinergic neurons, J. Comp. Neurol. 344:190–209.CrossRefGoogle Scholar
  24. Lavoie, B., and Parent, A., 1994b, Pedunculopontine nucleus in the squirrel monkey: cholinergic and glutamatergic projections to the substantia nigra, J. Comp. Neurol. 344:232–241.CrossRefGoogle Scholar
  25. Matsumura, M., Watanabe, K.. and Ohye. C, 1997, Single-unit activity in the primate nucleus tegmenti pedunculopontinus related to voluntary arm movement, Neurosci. Res. 28:155–165.PubMedCrossRefGoogle Scholar
  26. Mitchell, I. J., Clarke, C. E., Boyce, S., Robertson, R. G., Peggs, D., Sambrook, M. A., and Crossman, A. R., 1989, Neuronal mechanisms underlying parkinsonian symptoms based upon regional uptake of 2deoxyglucose in monkeys exposed to I -me thyl-4-phenyl-1,2,3.6-tetrahydropyridine, Neuroscience 32:213–226.PubMedCrossRefGoogle Scholar
  27. Nieoullon, A., and Kerkerian-Le Goff, L., 1992, Cellular interactions in the striatum involving neuronal systems using “classical” neurotransmitters: possible functional implications, Mov. Dis. 7:311–325.CrossRefGoogle Scholar
  28. Oakman, S. A., Faris, P. L., Kerr, P. E., Cozzari, C., and Hartman, B. K., 1995, Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differs significantly from those projecting to ventral tegmental area, J Neurosci. 15:5859–5869.PubMedGoogle Scholar
  29. Obeso, J. A., Guridi, J., Alvarez, L., Macias, R., and Linazasoro, G., 1998, Ablative surgery for Parkinson’s disease, in: Parkinson’s Disease and MOvenment Disorders, J. Jankovic and E. Tolosa, eds., Williams and Wilkins, Baltimore, pp. 1049–1064.Google Scholar
  30. Olney, J. W., 1988, Revelations in excitotoxicology, in: Frontiers in Excitatory Amino Acid Research, E. A. Cavalheiro, J. Lehmann and L. Turski, eds., Alan R. Liss, New York, pp. 589–596.Google Scholar
  31. Olney, J. W., 1989, Excitotoxicity and N-methyl-D-aspartate receptors, Drug Dev. Res, 17:299–319.CrossRefGoogle Scholar
  32. Palombo, E., Porrino, L. J., Bankiewicz, K. S., Crane, A. M., Sokoloff, L., and Kopin, I.J., 1990, Local cerebral glucose utilization in monkeys with hemiparkinsonism induced by intracarotid infusion of the neurotoxin MPTP, I Neurosci. 10:860–869.Google Scholar
  33. Scarnati, E., and Florio, T., 1997, The pedunculopontine nucleus and related structures: functional organization, in: The Basal Ganglia and New Surgical Approaches for Parkinson’s Disease, J. A. Obeso, M. R. DeLong, C. Ohye and C. D. Marsden, eds., Lippincott-Raven, Philadelphia, pp. 97–110.Google Scholar
  34. Schmidt, W. J., 1995, Balance of transmitter activities in the basal ganglia loops, J. Neural Transm. 46 (Suppl.):67–76.Google Scholar
  35. Smith, R. D., Zhang, Z., Kurlan, R., McDermott, M., and Gash, D. M. 1993, Developing a stable bilateral model of parkinsonism in rhesus monkeys, Neuroscience 52:7–16.PubMedCrossRefGoogle Scholar
  36. Smith, Y., Charara, A., and Parent, A., 1996, Synaptic innervation of midbrain dopaminergic neurons by glutamate-enriched terminals in the squirrel monkey, J. Comp. Neurot. 364:231–253.CrossRefGoogle Scholar
  37. Starr, M. S., 1995, Antiparkinsonian actions of glutamate antagonists — alone and with L-DOPA: a review of evidence and suggestions for possible mechanisms, J. Neural Transm. (Park. Dis. Dement. Sect.) 10:141–185.CrossRefGoogle Scholar
  38. Takakusaki, K., Shiroyama, T., Yamamoto, T., and Kitai, S. T., 1996, Cholinergic and noncholinergic tegmental pedunculopontine projection neurons in rats revealed by intracellular labeling, J. Conip. Neurot. 371:345–361.Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Masahiko Takada
    • 1
  • Masaru Matsumura
    • 2
  • Jun Kojima
    • 3
  • Yoshio Yamaji
    • 4
  • Masahiko Inase
    • 5
  • Hironobu Tokuno
    • 1
  • Atsushi Nambu
    • 1
  • Hisamasa Imai
    • 6
  1. 1.Tokyo Metropolitan Institute for NeuroscienceCREST, JST (Japan Science and Technology Corporation)TokyoJapan
  2. 2.Department of NeurosurgeryGunma University School of MedicineGunmaJapan
  3. 3.Department of NeurologySayama Neurology HospitalSaitamaJapan
  4. 4.Department of Public HealthJuntendo University School of MedicineTokyoJapan
  5. 5.Department of PhysiologyKinki University School of MedicineOsakaSayamaJapan
  6. 6.Department of NeurologyJuntendo University School of MedicineTokyoJapan

Personalised recommendations