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Glutamate Receptors and Parkinson’s Disease

Opportunities for Intervention

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Abstract

Parkinson’s disease is a debilitating neurodegenerative movement disorder that is the result of a degeneration of dopaminergic neurons in the substantia nigra pars compacta. The resulting loss of striatal dopaminergic tone is believed to underlie a series of changes in the circuitry of the basal ganglia that ultimately lead to severe motor disturbances due to excessive basal ganglia outflow. Glutamate plays a central role in the disruption of normal basal ganglia function, and it has been hypothesised that agents acting to restore normal glutamatergic function may provide therapeutic interventions that bypass the severe motor side effects associated with current dopamine replacement strategies. Analysis of the effects of glutamate receptor ligands in the basal ganglia circuit suggests that both ionotropic and metabotropic glutamate receptors could have antiparkinsonian actions. In particular, NMDA receptor antagonists that selectively target the NR2B subunit and antagonists of the metabotropic glutamate receptor mGluR5 appear to hold promise and deserve future attention.

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References

  1. Lang AE, Lozano AM. Parkinson’s Disease — first of two parts. N Engl J Med 1998; 339(15): 1044–53

    Article  PubMed  CAS  Google Scholar 

  2. Bennett DA, Beckett LA, Murray AM, et al. Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 1996; 334(2): 71–6

    Article  PubMed  CAS  Google Scholar 

  3. Hassler R. Zur Pathologie der Paralysis agitans und des postenzephalitischen Parkinsonismus. J Psychol Neurol 1938; 48: 387–476

    Google Scholar 

  4. Erhinger H, Homykiewicz O. Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin Wochenschr 1960; 38: 1236–9

    Article  Google Scholar 

  5. Jankovic J. Levodopa strengths and weaknesses. Neurology 2002; 58(90001): 19S–32

    Article  Google Scholar 

  6. DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990; 13(7): 281–5

    Article  PubMed  CAS  Google Scholar 

  7. Wichmann T, DeLong MR. Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg Clin N Am 1998; 9(2): 223–36

    PubMed  CAS  Google Scholar 

  8. Hollerman JR, Grace AA. Subthalamic nucleus cell firing in the 6-OHDA-treated rat: basal activity and response to haloperidol. Brain Res 1992; 590(1–2): 291–9

    Article  PubMed  CAS  Google Scholar 

  9. Bergman H, Wichmann T, Karmon B, et al. The primate subthalamic nucleus: II. neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 1994; 72(2): 507–20

    PubMed  CAS  Google Scholar 

  10. Hassani OK, Mouroux M, Feger J. Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus. Neuroscience 1996; 72(1): 105–15

    Article  PubMed  CAS  Google Scholar 

  11. Benazzouz A, Breit S, Koudsie A, et al. Intraoperative microrecordings of the subthalamic nucleus in Parkinson’s disease. Mov Disord 2002; 17Suppl. 3: S145–9

    Article  PubMed  Google Scholar 

  12. Rodriguez-Oroz MC, Rodriguez M, Guridi J, et al. The subthalamic nucleus in Parkinson’s disease: somatotopic organization and physiological characteristics. Brain 2001; 124 (Pt 9): 1777–90

    Article  PubMed  CAS  Google Scholar 

  13. Alvarez L, Macias R, Guridi J, et al. Dorsal subthalamotomy for Parkinson’s disease. Mov Disord 2001; 16(1): 72–8

    Article  PubMed  CAS  Google Scholar 

  14. Guridi J, Obeso JA. The subthalamic nucleus, hemiballismus and Parkinson’s disease: reappraisal of a neurosurgical dogma. Brain 2001; 124 (Pt 1): 5–19

    Article  PubMed  CAS  Google Scholar 

  15. Laitinen LV, Bergenheim AT, Hariz MI. Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992; 76(1): 53–61

    Article  PubMed  CAS  Google Scholar 

  16. Bakay RA, DeLong MR, Vitek JL. Posteroventral pallidotomy for Parkinson’s disease. J Neurosurg 1992; 77(3): 487–8

    PubMed  CAS  Google Scholar 

  17. Baron MS, Vitek JL, Bakay RA, et al. Treatment of advanced Parkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol 1996; 40(3): 355–66

    Article  PubMed  CAS  Google Scholar 

  18. Vitek JL, Bakay RA, Hashimoto T, et al. Microelectrodeguided pallidotomy: technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998; 88(6): 1027–43

    Article  PubMed  CAS  Google Scholar 

  19. Limousin P, Pollak P, Benazzouz A, et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995; 345(8942): 91–5

    Article  PubMed  CAS  Google Scholar 

  20. Deep-Brain Stimulation For Parkinson’s Disease Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med 2001; 345(13): 956–63

    Article  Google Scholar 

  21. Blandini F, Nappi G, Tassorelli C, et al. Functional changes of the basal ganglia circuitry in Parkinson’s disease. Prog Neurobiol 2000; 62(1): 63–88

    Article  PubMed  CAS  Google Scholar 

  22. Borges K, Dingledine R. AMPA receptors: molecular and functional diversity. Prog Brain Res 1998; 116: 153–70

    Article  PubMed  CAS  Google Scholar 

  23. Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 1997; 37: 205–37

    Article  PubMed  CAS  Google Scholar 

  24. Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels. Pharmacol Rev 1999; 51(1): 7–61

    PubMed  CAS  Google Scholar 

  25. Rouse ST, Marino MJ, Bradley SR, et al. Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson’s disease and related disorders. Pharmacol Ther 2000; 88(3): 427–35

    Article  PubMed  CAS  Google Scholar 

  26. Smith Y, Charara A, Paquet M, et al. Ionotropic and metabotropic GABA and glutamate receptors in primate basal ganglia. J Chem Neuroanat 2001; 22(1–2): 13–42

    Article  PubMed  CAS  Google Scholar 

  27. Malenka RC, Nicoll RA. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci 1993; 16(12): 521–7

    Article  PubMed  CAS  Google Scholar 

  28. Morris RG, Davis S, Butcher SP. Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Philos Trans R Soc Lond B Biol Sci 1990; 329(1253): 187–204

    Article  PubMed  CAS  Google Scholar 

  29. Cotman CW, Monaghan DT, Ganong AH. Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity. Annu Rev Neurosci 1988; 11: 61–80

    Article  PubMed  CAS  Google Scholar 

  30. Contestabile A. Roles of NMDA receptor activity and nitric oxide production in brain development. Brain Res Brain Res Rev 2000; 32(2–3): 476–509

    Article  PubMed  CAS  Google Scholar 

  31. Scheetz AJ, Constantine-Paton M. Modulation of NMDA receptor function: implications for vertebrate neural development. FASEB J 1994; 8(10): 745–52

    PubMed  CAS  Google Scholar 

  32. Mody I, MacDonald JF. NMDA receptor-dependent excitotoxicity: the role of intracellular Ca2+ release. Trends Pharmacol Sci 1995; 16(10): 356–9

    Article  PubMed  CAS  Google Scholar 

  33. Rothman SM, Olney JW. Excitotoxicity and the NMDA receptor: still lethal after eight years. Trends Neurosci 1995; 18(2): 57–8

    Article  PubMed  CAS  Google Scholar 

  34. Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 1987; 325(6104): 529–31

    Article  PubMed  CAS  Google Scholar 

  35. Johnson JW, Ascher P. Equilibrium and kinetic study of glycine action on the N-methyl-D-aspartate receptor in cultured mouse brain neurons. J Physiol 1992; 455: 339–65

    PubMed  CAS  Google Scholar 

  36. Laube B, Hirai H, Sturgess M, et al. Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron 1997; 18(3): 493–503

    Article  PubMed  CAS  Google Scholar 

  37. Anson LC, Chen PE, Wyllie DJ, et al. Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors. J Neurosci 1998; 18(2): 581–9

    PubMed  CAS  Google Scholar 

  38. Kuryatov A, Laube B, Betz H, et al. Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins. Neuron 1994: 12(6): 1291–300

    Article  PubMed  CAS  Google Scholar 

  39. Wafford KA, Kathoria M, Bain CJ, et al. Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site. Mol Pharmacol 1995; 47(2): 374–80

    PubMed  CAS  Google Scholar 

  40. Hirai H, Kirsch J, Laube B, et al. The glycine binding site of the N-methyl-D-aspartate receptor subunit NR1: identification of novel determinants of co-agonist potentiation in the extracellular M3-M4 loop region. Proc Natl Acad Sci U S A 1996; 93(12): 6031–6

    Article  PubMed  CAS  Google Scholar 

  41. Williams K, Chao J, Kashiwagi K, et al. Activation of N-methyl-D-aspartate receptors by glycine: role of an aspartate residue in the M3-M4 loop of the NR1 subunit. Mol Pharmacol 1996; 50(4): 701–8

    PubMed  CAS  Google Scholar 

  42. Wood MW, VanDongen HM, VanDongen AM. An alanine residue in the M3-M4 linker lines the glycine binding pocket of the N-methyl-D-aspartate receptor. J Biol Chem 1997; 272(6): 3532–7

    Article  PubMed  CAS  Google Scholar 

  43. Ascher P, Bregestovski P, Nowak L. N-methyl-D-aspartateactivated channels of mouse central neurones in magnesium-free solutions. J Physiol 1988; 399: 207–26

    PubMed  CAS  Google Scholar 

  44. Mayer ML, Westbrook GL. Permeation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse cultured central neurones. J Physiol 1987; 394: 501–27

    PubMed  CAS  Google Scholar 

  45. Mayer ML, Westbrook GL. The action of N-methyl-D-aspartic acid on mouse spinal neurones in culture. J Physiol 1985; 361: 65–90

    PubMed  CAS  Google Scholar 

  46. Ascher P, Nowak L. The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture. J Physiol 1988; 399: 247–66

    PubMed  CAS  Google Scholar 

  47. Nowak L, Bregestovski P, Ascher P, et al. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 1984; 307(5950): 462–5

    Article  PubMed  CAS  Google Scholar 

  48. Tsien JZ. Linking Hebb’s coincidence-detection to memory formation. Curr Opin Neurobiol 2000; 10(2): 266–73

    Article  PubMed  CAS  Google Scholar 

  49. Seeburg PH, Burnashev N, Kohr G, et al. The NMDA receptor channel: molecular design of a coincidence detector. Recent Prog Horm Res 1995; 50: 19–34

    PubMed  CAS  Google Scholar 

  50. Pisani A, Calabresi P, Centonze D, et al. Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. Br J Pharmacol 1997; 120(6): 1007–14

    Article  PubMed  CAS  Google Scholar 

  51. Gotz T, Kraushaar U, Geiger J, et al. Functional properties of AMPA and NMDA receptors expressed in identified types of basal ganglia neurons. J Neurosci 1997; 17(1): 204–15

    PubMed  CAS  Google Scholar 

  52. Awad H, Hubert GW, Smith Y, et al. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 2000; 20(21): 7871–9

    PubMed  CAS  Google Scholar 

  53. Marino MJ, Hubert GW, Smith Y, et al. Functional roles of group I metabotropic glutamate receptors in the substantia nigra pars reticulata [abstract]. Soc Neurosci 2000; 30(16): 740

    Google Scholar 

  54. Starr MS. Antiparkinsonian actions of glutamate antagonists, alone and with LEVODOPA: a review of evidence and suggestions for possible mechanisms. J Neural Transm Park Dis Dement Sect 1995; 10(2–3): 141–85

    PubMed  CAS  Google Scholar 

  55. Williams K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol 1993; 44(4): 851–9

    PubMed  CAS  Google Scholar 

  56. Avenet P, Leonardon J, Besnard F, et al. Antagonist properties of eliprodil and other NMDA receptor antagonists at rat NR1A/NR2A and NR1A/NR2B receptors expressed in Xe-nopus oocytes. Neurosci Lett 1997; 223(2): 133–6

    Article  PubMed  CAS  Google Scholar 

  57. Gallagher MJ, Huang H, Pritchett DB, et al. Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 1996; 271(16): 9603–11

    Article  PubMed  CAS  Google Scholar 

  58. Menniti F, Chenard B, Collins M, et al. CP-101,606, a potent neuroprotectant selective for forebrain neurons. Eur J Pharmacol 1997; 331(2–3): 117–26

    Article  PubMed  CAS  Google Scholar 

  59. Chenard BL, Bordner J, Butler TW, et al. (lS,2S)-l-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-l-propanol: apotent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem 1995; 38(16): 3138–45

    Article  PubMed  CAS  Google Scholar 

  60. Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol 1989; 166(3): 591–2

    Article  PubMed  CAS  Google Scholar 

  61. Kornhuber J, Weiler M, Schoppmeyer K, et al. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl 1994; 43: 91–104

    PubMed  CAS  Google Scholar 

  62. Klockgether T, Jacobsen P, Loschmann PA, et al. The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist. J Neural Transm Park Dis Dement Sect 1993; 5(2): 101–6

    Article  PubMed  CAS  Google Scholar 

  63. Parsons CG, Hartmann S, Spielmanns P. Budipine is a low affinity, N-methyl-D-aspartate receptor antagonist: patch clamp studies in cultured striatal, hippocampal, cortical and superior colliculus neurones. Neuropharmacology 1998; 37(6): 719–27

    Article  PubMed  CAS  Google Scholar 

  64. Kornhuber J, Herr B, Thome J, et al. The antiparkinsonian drug budipine binds to NMDA and sigma receptors in postmortem human brain tissue. J Neural Transm Suppl 1995; 46: 131–7

    PubMed  CAS  Google Scholar 

  65. Jackisch R, Kruchen A, Sauermann W, et al. The antiparkinsonian drugs budipine and biperiden are use-dependent (uncompetitive) NMDA receptor antagonists. Eur J Pharmacol 1994; 264(2): 207–11

    Article  PubMed  CAS  Google Scholar 

  66. Steece-Collier K, Chambers LK, Jaw-Tsai SS, et al. Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunitcontaining N-methyl-d-aspartate receptors. Exp Neurol 2000; 163(1): 239–43

    Article  PubMed  CAS  Google Scholar 

  67. Bubser M, Zadow B, Kronthaler UO, et al. Behavioural pharmacology of the non-competitive NMDA antagonists dextrorphan and ADCI: relations between locomotor stimulation, anticataleptic potential and forebrain dopamine metabolism. Naunyn Schmiedebergs Arch Pharmacol 1997; 355(6): 767–73

    Article  PubMed  CAS  Google Scholar 

  68. Kaur S, Ozer H, Starr M. MK 801 reverses haloperidol-induced catalepsy from both striatal and extrastriatal sites in the rat brain. Eur J Pharmacol 1997; 332(2): 153–60

    Article  PubMed  CAS  Google Scholar 

  69. McAllister KH. The competitive NMDA receptor antagonist SDZ 220-581 reverses haloperidol-induced catalepsy in rats. Eur J Pharmacol 1996; 314(3): 307–11

    Article  PubMed  CAS  Google Scholar 

  70. Moore NA, Blackman A, Awere S, et al. NMDA receptor antagonists inhibit catalepsy induced by either dopamine Dl or D2 receptor antagonists. Eur J Pharmacol 1993; 237(1): 1–7

    Article  PubMed  CAS  Google Scholar 

  71. Nash JE, Hill MP, Brotchie JM. Antiparkinsonian actions of blockade of NR2B-containing NMDA receptors in the reserpine-treated rat. Exp Neurol 1999; 155(1): 42–8

    Article  PubMed  CAS  Google Scholar 

  72. Kaur S, Starr MS. Antiparkinsonian action of dextromethorphan in the reserpine-treated mouse. Eur J Pharmacol 1995; 280(2): 159–66

    Article  PubMed  CAS  Google Scholar 

  73. Ossowska K, Lorenc-Koci E, Wolfarth S. Antiparkinsonian action of MK-801 on the reserpine-induced rigidity: a mechanomyographic analysis. J Neural Transm Park Dis Dement Sect 1994; 7(2): 143–52

    Article  PubMed  CAS  Google Scholar 

  74. Skuza G, Rogoz Z, Quack G, et al. Memantine, amantadine, and L-deprenyl potentiate the action of levodopa in monoaminedepleted rats. J Neural Transm Gen Sect 1994; 98(1): 57–67

    Article  PubMed  CAS  Google Scholar 

  75. Greenberg DA. Glutamate and Parkinson’s disease. Ann Neurol 1994; 35(6): 639

    Article  PubMed  CAS  Google Scholar 

  76. Carlsson M, Carlsson A. Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice. J Neural Transm 1989; 77(1): 65–71

    Article  PubMed  CAS  Google Scholar 

  77. Stauch-Slusher B, Rissolo KC, Jackson PF, et al. Centrally-administered glycine antagonists increase locomotion in monoamine-depleted mice. J Neural Transm Gen Sect 1994; 97(3): 175–85

    Article  PubMed  CAS  Google Scholar 

  78. Karcz-Kubicha M, Lorenz B, Danysz W. GlycineB antagonists and partial agonists in rodent models of Parkinson’s disease: comparison with uncompetitive N-methyl-D-aspartate receptor antagonist. Neuropharmacology 1999; 38(1): 109–19

    Article  PubMed  CAS  Google Scholar 

  79. Kretschmer BD, Zadow B, Volz TL, et al. The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior. J Neural Transm Gen Sect 1992; 87(1): 23–35

    Article  PubMed  CAS  Google Scholar 

  80. Kretschmer BD, Koch M. Role of the strychnine-insensitive glycine binding site in the nucleus accumbens and anterodorsal striatum in sensorimotor gating: a behavioral and microdialysis study. Psychopharmacology 1997; 130(2): 131–8

    Article  PubMed  CAS  Google Scholar 

  81. Mokry J. Experimental models and behavioural tests used in the study of Parkinson’s disease. Physiol Res 1995; 44(3): 143–50

    PubMed  CAS  Google Scholar 

  82. Klockgether T, Wullner U, Steinbach JP, et al. Effects of the antiparkinsonian drug budipine on central neurotransmitter systems. Eur J Pharmacol 1996; 301(1–3): 67–73

    Article  PubMed  CAS  Google Scholar 

  83. St Pierre JA, Bedard PJ. Systemic administration of the NMDA receptor antagonist MK-801 potentiates circling induced by intrastriatal microinjection of dopamine. Eur J Pharmacol 1995; 272(2–3): 123–9

    Article  PubMed  CAS  Google Scholar 

  84. Loschmann PA, Wullner U, Heneka MT, et al. Differential interaction of competitive NMDA and AMPA antagonists with selective dopamine D-1 and D-2 agonists in a rat model of Parkinson’s disease. Synapse 1997; 26(4): 381–91

    Article  PubMed  CAS  Google Scholar 

  85. Marin C, Papa S, Engber TM, et al. MK-801 prevents levodopainduced motor response alterations in parkinsonian rats. Brain Res 1996; 736(1–2): 202–5

    Article  PubMed  CAS  Google Scholar 

  86. Engber TM, Papa SM, Boldry RC, et al. NMDA receptor blockade reverses motor response alterations induced by levodopa. Neuroreport 1994; 5(18): 2586–8

    Article  PubMed  CAS  Google Scholar 

  87. Schmidt WJ, Kretschmer BD. Behavioural pharmacology of glutamate receptors in the basal ganglia. Neurosci Biobehav Rev 1997; 21(4): 381–92

    Article  PubMed  CAS  Google Scholar 

  88. Di Chiara G, Morelli M, Consolo S. Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions. Trends Neurosci 1994; 17(6): 228–33

    Article  PubMed  Google Scholar 

  89. Carlsson M, Carlsson A. Interactions between glutamatergic and monoaminergic systems within the basal ganglia: implications for schizophrenia and Parkinson’s disease. Trends Neurosci 1990; 13(7): 272–6

    Article  PubMed  CAS  Google Scholar 

  90. Morelli M, Fenu S, Pinna A, et al. Opposite effects of NMDA receptor blockade on dopaminergic D1- and D2-mediated behavior in the 6-hydroxydopamine model of turning: relationship with c-fos expression. J Pharmacol Exp Ther 1992; 260(1): 402–8

    PubMed  CAS  Google Scholar 

  91. Morelli M, Di Chiara G. MK-801 potentiates dopaminergic D1 but reduces D2 responses in the 6-hydroxydopamine model of Parkinson’s disease. Eur J Pharmacol 1990; 182(3): 611–2

    Article  PubMed  CAS  Google Scholar 

  92. Carlsson M, Carlsson A. The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 1989; 75(3): 221–6

    Article  PubMed  CAS  Google Scholar 

  93. Dunah AW, Wang Y, Yasuda RP, et al. Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson’s disease. Mol Pharmacol 2000; 57(2): 342–52

    PubMed  CAS  Google Scholar 

  94. Dunah AW, Standaert DG. Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J Neurosci 2001; 21(15): 5546–58

    PubMed  CAS  Google Scholar 

  95. Ganguly A, Keefe KA. Unilateral dopamine depletion increases expression of the 2A subunit of the N-methyl-D-aspartate receptor in enkephalin-positive and enkephalin-negative neurons. Neuroscience 2001; 103(2): 405–12

    Article  PubMed  CAS  Google Scholar 

  96. Meshul CK, Emre N, Nakamura CM, et al. Time-dependent changes in striatal glutamate synapses following a 6-hydroxydopamine lesion. Neuroscience 1999; 88(1): 1–16

    Article  PubMed  CAS  Google Scholar 

  97. Graham WC, Robertson RG, Sambrook MA, et al. Injection of excitatory amino acid antagonists into the medial pallidal segment of a l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) treated primate reverses motor symptoms of parkinsonism. Life Sci 1990; 47(18): L91–7

    Article  Google Scholar 

  98. Crossman AR, Peggs D, Boyce S, et al. Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey. Neuropharmacology 1989; 28(11): 1271–3

    Article  PubMed  CAS  Google Scholar 

  99. Blanchet PJ, Konitsiotis S, Whittemore ER, et al. Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys. J Pharmacol Exp Ther 1999; 290(3): 1034–40

    PubMed  CAS  Google Scholar 

  100. Greenamyre JT, Eller RV, Zhang Z, et al. Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist, in rodent and primate models of Parkinson’s disease. Ann Neurol 1994; 35(6): 655–61

    Article  PubMed  CAS  Google Scholar 

  101. Loschmann PA, Lange KW, Kunow M, et al. Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with Levodopa in models of Parkinson’s disease. J Neural Transm Park Dis Dement Sect 1991; 3(3): 203–13

    Article  PubMed  CAS  Google Scholar 

  102. Papa SM, Chase TN. Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Ann Neurol 1996; 39(5): 574–8

    Article  PubMed  CAS  Google Scholar 

  103. Avenet P, Leonardon J, Besnard F, et al. Antagonist properties of the stereoisomers of ifenprodil at NR1A/NR2A and NR1A/NR2B subtypes of the NMDA receptor expressed in Xenopus oocytes. Eur J Pharmacol 1996; 296(2): 209–13

    Article  PubMed  CAS  Google Scholar 

  104. Kuppenbender KD, Standaert DG, Feuerstein TJ, et al. Expression of NMDA receptor subunit mRNAs in neurochemically identified projection and interneurons in the human striatum. J Comp Neurol 2000; 419(4): 407–21

    Article  PubMed  CAS  Google Scholar 

  105. Kosinski CM, Standaert DG, Counihan TJ, et al. Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: striatum and globus pallidus. J Comp Neurol 1998; 390(1): 63–74

    Article  PubMed  CAS  Google Scholar 

  106. Schito AM, Pizzuti A, Di Maria E, et al. mRNA distribution in adult human brain of GRIN2B, a N-methyl-D-aspartate (NMDA) receptor subunit. Neurosci Lett 1997; 239(1): 49–53

    Article  PubMed  CAS  Google Scholar 

  107. Jin DH, Jung YW, Ko BH, et al. Immunoblot analyses on the differential distribution of NR2A and NR2B subunits in the adult rat brain. Mol Cells 1997; 7(6): 749–54

    PubMed  CAS  Google Scholar 

  108. Nash JE, Fox SH, Henry B, et al. Antiparkinsonian actions of ifenprodil in the MPTP-lesioned marmoset model of Parkinson’s disease. Exp Neurol 2000; 165(1): 136–42

    Article  PubMed  CAS  Google Scholar 

  109. Mitchell IJ, Carroll CB. Reversal of parkinsonian symptoms in primates by antagonism of excitatory amino acid transmission: potential mechanisms of action. Neurosci Biobehav Rev 1997; 21(4): 469–75

    Article  PubMed  CAS  Google Scholar 

  110. Montastruc JL, Rascol O, Senard JM, et al. A pilot study of N-methyl-D-aspartate (NMDA) antagonist in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992; 55(7): 630–1

    Article  PubMed  CAS  Google Scholar 

  111. Schwab RS, England Jr AC, Poskanzer DC, et al. Amantadine in the treatment of Parkinson’s disease. JAMA 1969; 208(7): 1168–70

    Article  PubMed  CAS  Google Scholar 

  112. Fischer PA, Jacobi P, Schneider E, et al. Effects of intravenous administration of memantine in parkinsonian patients. Arzneimittelforschung 1977; 27(7): 1487–9

    PubMed  CAS  Google Scholar 

  113. Kornhuber J, Bormann J, Retz W, et al. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol 1989; 166(3): 589–90

    Article  PubMed  CAS  Google Scholar 

  114. Kornhuber J, Bormann J, Hubers M, et al. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol 1991; 206(4): 297–300

    Article  PubMed  CAS  Google Scholar 

  115. Kornhuber J, Quack G, Danysz W, et al. Therapeutic brain concentration of the NMDA receptor antagonist amantadine. Neuropharmacology 1995; 34(7): 713–21

    Article  PubMed  CAS  Google Scholar 

  116. Del Dotto P, Pavese N, Gambaccini G, et al. Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study. Mov Disord 2001; 16(3): 515–20

    Article  PubMed  Google Scholar 

  117. Snow BJ, Macdonald L, Mcauley D, et al. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol 2000; 23(2): 82–5

    Article  PubMed  CAS  Google Scholar 

  118. Verhagen-Metman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 1998; 50(5): 1323–6

    Article  PubMed  CAS  Google Scholar 

  119. Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol 1999; 56(11): 1383–6

    Article  PubMed  CAS  Google Scholar 

  120. Merello M, Nouzeilles MI, Cammarota A, et al. Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin Neuropharmacol 1999; 22(5): 273–6

    PubMed  CAS  Google Scholar 

  121. Rabey JM, Nissipeanu P, Korczyn AD. Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson’s disease. J Neural Transm Park Dis Dement Sect 1992; 4: 277–82

    Article  PubMed  CAS  Google Scholar 

  122. Schneider E, Fischer PA, Clemens R, et al. Wirkungen oraler Memantin-Gaben auf die Parkinson-Symptomatik. Ergebnisse einer placebo-kontrollierten Multicenter-Studie. Dtsch Med Wochenschr 1984; 109(25): 987–90

    Article  PubMed  CAS  Google Scholar 

  123. Fischer PA, Jacobi P, Schneider E, et al. Die Wirkung intravenoser Gaben von Memantin bei Parkinson-Kranken. Arzneimittelforschung 1977; 27(7): 1487–9

    PubMed  CAS  Google Scholar 

  124. Maisch U, Bliesath H, Bother K, et al. Monotherapie der Parkinsonschen Erkrankung mit Budipin. Ein randomisierter Doppelblindvergleich mit Amantadin. Fortschr Neurol Psychiatr 2001; 69(2): 86–9

    Article  Google Scholar 

  125. Spieker S, Loschmann PA, Klockgether T. The NMDA antagonist budipine can alleviate levodopa-induced motor fluctuations. Mov Disord 1999; 14(3): 517–9

    Article  PubMed  CAS  Google Scholar 

  126. Jellinger K, Bliesath H. Adjuvant treatment of Parkinson’s disease with budipine: a double-blind trial versus placebo. J Neurol 1987; 234(5): 280–2

    Article  PubMed  CAS  Google Scholar 

  127. Verhagen-Metman L, Del Dotto P, Natte R, et al. Dextromethorphan improves levodopa-induced dyskinesias in Parkinson’s disease. Neurology 1998; 51(1): 203–6

    Article  PubMed  CAS  Google Scholar 

  128. Verhagen-Metman L, Blanchet PJ, van den Munckhof P, et al. A trial of dextromethorphan in parkinsonian patients with motor response complications. Mov Disord 1998; 13(3): 414–7

    Article  PubMed  CAS  Google Scholar 

  129. Blanchet PJ, Metman LV, Mouradian MM, et al. Acute pharmacologic blockade of dyskinesias in Parkinson’s disease. Mov Disord 1996; 11(5): 580–1

    Article  PubMed  CAS  Google Scholar 

  130. Kieburtz K, Feigin A, McDermott M, et al. A controlled trial of remacemide hydrochloride in Huntington’s disease. Mov Disord 1996; 11(3): 273–7

    Article  PubMed  CAS  Google Scholar 

  131. Richens A, Mawer G, Crawford P, et al. A placebo-controlled, double-blind cross-over trial of adjunctive one month remacemide hydrochloride treatment in patients with refractory epilepsy. Seizure 2000; 9(8): 537–43

    Article  PubMed  CAS  Google Scholar 

  132. Dyker AG, Lees KR. Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke. Stroke 1999; 30(9): 1796–801

    Article  PubMed  CAS  Google Scholar 

  133. Palmer GC, Murray RJ, Wilson TC, et al. Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide. Epilepsy Res 1992; 12(1): 9–20

    Article  PubMed  CAS  Google Scholar 

  134. Clarke CE, Cooper JA, Holdich TA. A randomized, double-blind, placebo-controlled, ascending-dose tolerability and safety study of remacemide as adjuvant therapy in Parkinson’s disease with response fluctuations. Clin Neuropharmacol 2001; 24(3): 133–8

    Article  PubMed  CAS  Google Scholar 

  135. Parkinson-Study-Group. A multicenter randomized controlled trial of remacemide hydrochloride as monotherapy for PD: Parkinson Study Group. Neurology 2000; 54(8): 1583–8

    Article  Google Scholar 

  136. Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson’s disease. Neurology 2001; 56(4): 455–62

    Article  PubMed  CAS  Google Scholar 

  137. Parkinson-Study-Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease. Arch Neurol 2001; 58(10): 1660–8

    Article  Google Scholar 

  138. Danysz W, Parsons AC. Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 1998; 50(4): 597–664

    PubMed  CAS  Google Scholar 

  139. Giuffra ME, Sethy VH, Davis TL, et al. Milacemide therapy for Parkinson’s disease. Mov Disord 1993; 8(1): 47–50

    Article  PubMed  CAS  Google Scholar 

  140. Jonas P, Racca C, Sakmann B, et al. Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression. Neuron 1994; 12(6): 1281–9

    Article  PubMed  CAS  Google Scholar 

  141. Burnashev N, Monyer H, Seeburg PH, et al. Divalent ion-permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 1992; 8(1): 189–98

    Article  PubMed  CAS  Google Scholar 

  142. Muller T, Moller T, Berger T, et al. Calcium entry through kainate receptors and resulting potassium-channel blockade in Bergmann glial cells. Science 1992; 256(5063): 1563–6

    Article  PubMed  CAS  Google Scholar 

  143. Hollmann M, Hartley M, Heinemann S. Ca2+ permeability of KA-AMPA: gated glutamate receptor channels depends on subunit composition. Science 1991; 252(5007): 851–3

    Article  PubMed  CAS  Google Scholar 

  144. Rueter SM, Burns CM, Coode SA, et al. Glutamate receptor RNA editing in vitro by enzymatic conversion of adenosine to inosine. Science 1995; 267(5203): 1491–4

    Article  PubMed  CAS  Google Scholar 

  145. Washburn MS, Dingledine R. Block of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by polyamines and polyamine toxins. J Pharmacol Exp Ther 1996; 278(2): 669–78

    PubMed  CAS  Google Scholar 

  146. Swanson GT, Feldmeyer D, Kaneda M, et al. Effect of RNA editing and subunit co-assembly single-channel properties of recombinant kainate receptors. J Physiol 1996; 492 (Pt 1): 129–42

    PubMed  CAS  Google Scholar 

  147. Herlitze S, Raditsch M, Ruppersberg JP, et al. Argiotoxin detects molecular differences in AMPA receptor channels. Neuron 1993; 10(6): 1131–40

    Article  PubMed  CAS  Google Scholar 

  148. Brackley PT, Bell DR, Choi SK, et al. Selective antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins. J Pharmacol Exp Ther 1993; 266(3): 1573–80

    PubMed  CAS  Google Scholar 

  149. Tanaka H, Grooms SY, Bennett MV, et al. The AMP AR subunit GluR2: still front and center-stage. Brain Res 2000; 886(1–2): 190–207

    Article  PubMed  CAS  Google Scholar 

  150. Myers SJ, Dingledine R, Borges K. Genetic regulation of glutamate receptor ion channels. Annu Rev Pharmacol Toxicol 1999; 39: 221–41

    Article  PubMed  CAS  Google Scholar 

  151. Pellegrini-Giampietro DE, Gorter JA, Bennett MV, et al. The GluR2 (GluR-B) hypothesis: Ca (2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci 1997; 20(10): 464–70

    Article  PubMed  CAS  Google Scholar 

  152. Betarbet R, Porter RH, Greenamyre JT. GluRl glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation. J Neurochem 2000; 74(3): 1166–74

    Article  PubMed  CAS  Google Scholar 

  153. He Y, Lee T, Leong SK. Effect of 6-OHDA injection on the AMPA glutamate receptor subunits in the substantia nigra of Sprague-Dawley rats. Neurosci Lett 1998; 241(1): 1–4

    Article  PubMed  CAS  Google Scholar 

  154. Bernard V, Gardiol A, Faucheux B, et al. Expression of glutamate receptors in the human and rat basal ganglia: effect of the dopaminergic denervation on AMPA receptor gene expression in the striatopallidal complex in Parkinson’s disease and rat with 6-OHDA lesion. J Comp Neurol 1996; 368(4): 553–68

    Article  PubMed  CAS  Google Scholar 

  155. Arnt J. Turning behaviour and catalepsy after injection of excitatory amino acids into rat substantia nigra. Neurosci Lett 1981; 23(3): 337–42

    Article  PubMed  CAS  Google Scholar 

  156. Turski W, Turski L, Czuczwar SJ, et al. (RS)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid: wet dog shakes, catalepsy and body temperature changes in rats. Pharmacol Biochem Behav 1981; 15(4): 545–9

    Article  PubMed  CAS  Google Scholar 

  157. Wachtel H, Kunow M, Loschmann PA. NBQX (6-nitro-sulfamoyl-benzo-quinoxaline-dione) and CPP (3-carboxy-pi-perazin-propyl phosphonic acid) potentiate dopamine agonist induced rotations in substantia nigra lesioned rats. Neurosci Lett 1992; 142(2): 179–82

    Article  PubMed  CAS  Google Scholar 

  158. Loschmann PA, Kunow M, Wachtel H. Synergism of NBQX with dopamine agonists in the 6-OHDA rat model of Parkinson’s disease. J Neural Transm Suppl 1992; 38: 55–64

    PubMed  CAS  Google Scholar 

  159. Zadow B, Schmidt WJ. The AMPA antagonists NBQX and GYKI 52466 do not counteract neuroleptic-induced catalepsy. Naunyn Schmiedebergs Arch Pharmacol 1994; 349(1): 61–5

    Article  PubMed  CAS  Google Scholar 

  160. Papa SM, Engber TM, Boldry RC, et al. Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists. Eur J Pharmacol 1993; 232(2–3): 247–53

    Article  PubMed  CAS  Google Scholar 

  161. Maj J, Rogoz Z, Skuza G, et al. Some central effects of GYKI 52466, a non-competitive AMPA receptor antagonist. Pol J Pharmacol 1995; 47(6): 501–7

    PubMed  CAS  Google Scholar 

  162. Konitsiotis S, Blanchet PJ, Verhagen L, et al. AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys. Neurology 2000; 54(8): 1589–95

    Article  PubMed  CAS  Google Scholar 

  163. Marin C, Jimenez A, Bonastre M, et al. Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in Parkinsonian rats. Synapse 2000; 36(4): 267–74

    Article  PubMed  CAS  Google Scholar 

  164. Marin C, Jimenez A, Bonastre M, et al. LY293558, an AMPA glutamate receptor antagonist, prevents and reverses levodopainduced motor alterations in Parkinsonian rats. Synapse 2001; 42(1): 40–7

    Article  PubMed  CAS  Google Scholar 

  165. Klockgether T, Turski L, Honore T, et al. The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys. Ann Neurol 1991; 30(5): 717–23

    Article  PubMed  CAS  Google Scholar 

  166. Luquin MR, Obeso JA, Laguna J, et al. The AMPA receptor antagonist NBQX does not alter the motor response induced by selective dopamine agonists in MPTP-treated monkeys. Eur J Pharmacol 1993; 235(2–3): 297–300

    Article  PubMed  CAS  Google Scholar 

  167. Rodriguez-Moreno A, Lopez-Garcia JC, Lerma J. Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons. Proc Natl Acad Sci U S A 2000; 97(3): 1293–8

    Article  PubMed  CAS  Google Scholar 

  168. Rodriguez-Moreno A, Lerma J. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 1998; 20(6): 1211–8

    Article  PubMed  CAS  Google Scholar 

  169. Rodriguez-Moreno A, Herreras O, Lerma J. Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus. Neuron 1997; 19(4): 893–901

    Article  PubMed  CAS  Google Scholar 

  170. Charara A, Blankstein E, Smith Y. Presynaptic kainate receptors in the monkey striatum. Neuroscience 1999; 91(4): 1195–200

    Article  PubMed  CAS  Google Scholar 

  171. Kieval JZ, Hubert GW, Charara A, et al. Subcellular and subsynaptic localization of presynaptic and postsynaptic kainate receptor subunits in the monkey striatum. J Neurosci 2001; 21(22): 8746–57

    PubMed  CAS  Google Scholar 

  172. Sherer TB, Betarbet R, Greenamyre JT. Pathogenesis of Parkinson’s disease. Curr Opin Investig Drugs 2001; 2(5): 657–62

    PubMed  CAS  Google Scholar 

  173. Beal MF. Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 2000; 23(7): 298–304

    Article  PubMed  CAS  Google Scholar 

  174. Zhang Y, Dawson VL, Dawson TM. Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol Dis 2000; 7(4): 240–50

    Article  PubMed  CAS  Google Scholar 

  175. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine. Life Sci 1985: 36(26): 2503–8

    Article  PubMed  CAS  Google Scholar 

  176. Yoshino H, Nakagawa-Hattori Y, Kondo T, et al. Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson’s disease. J Neural Transm Park Dis Dement Sect 1992; 4(1): 27–34

    Article  PubMed  CAS  Google Scholar 

  177. Krige D, Carroll MT, Cooper JM, et al. Platelet mitochondrial function in Parkinson’s disease. The Royal Kings and Queens Parkinson Disease Research Group. Ann Neurol 1992; 32(6): 782–8

    Article  PubMed  CAS  Google Scholar 

  178. Schapira AH, Cooper JM, Dexter D, et al. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54(3): 823–7

    Article  PubMed  CAS  Google Scholar 

  179. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989; 26(6): 719–23

    Article  PubMed  Google Scholar 

  180. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 1999; 81(3): 163–221

    Article  PubMed  CAS  Google Scholar 

  181. Massieu L, Garcia O. The role of excitotoxicity and metabolic failure in the pathogenesis of neurological disorders. Neurobiology (Bp) 1998; 6(1): 99–108

    CAS  Google Scholar 

  182. Ikonomidou C, Turski L. Excitotoxicity and neurodegenerative diseases. Curr Opin Neurol 1995; 8(6): 487–97

    Article  PubMed  CAS  Google Scholar 

  183. Beal MF. Role of excitotoxicity in human neurological disease. Curr Opin Neurobiol 1992; 2(5): 657–62

    Article  PubMed  CAS  Google Scholar 

  184. Albin RL, Greenamyre JT. Alternative excitotoxic hypotheses. Neurology 1992; 42(4): 733–8

    Article  PubMed  CAS  Google Scholar 

  185. Beal MF, Hyman BT, Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci 1993; 16(4): 125–31

    Article  PubMed  CAS  Google Scholar 

  186. Erecinska M, Dagani F. Relationships between the neuronal sodium/potassium pump and energy metabolism: Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes. J Gen Physiol 1990; 95(4): 591–616

    Article  PubMed  CAS  Google Scholar 

  187. Novelli A, Reilly JA, Lysko PG, et al. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res 1988; 451(1–2): 205–12

    Article  PubMed  CAS  Google Scholar 

  188. Kita H, Kitai ST. Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method. J Comp Neurol 1987; 260(3): 435–52

    Article  PubMed  CAS  Google Scholar 

  189. Smith ID, Grace AA. Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity. Synapse 1992: 12(4): 287–303

    Article  PubMed  CAS  Google Scholar 

  190. Iribe Y, Moore K, Pang KC, et al. Subthalamic stimulation-induced synaptic responses in substantia nigra pars compacta dopaminergic neurons in vitro. J Neurophysiol 1999; 82(2): 925–33

    PubMed  CAS  Google Scholar 

  191. Rodriguez MC, Obeso JA, Olanow CW. Subthalamic nucleus-mediated excitotoxicity in Parkinson’s disease: a target for neuroprotection. Ann Neurol. 1998; 44 (3 Suppl. 1): S175–88

    PubMed  CAS  Google Scholar 

  192. Piallat B, Benazzouz A, Benabid AL. Subthalamic nucleus lesion in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: behavioural and immunohistochemical studies. Eur J Neurosci 1996; 8(7): 1408–14

    Article  PubMed  CAS  Google Scholar 

  193. Turski L, Bressler K, Rettig KJ, et al. Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists. Nature 1991; 349(6308): 414–8

    Article  PubMed  CAS  Google Scholar 

  194. Sonsalla PK, Zeevalk GD, Manzino L, et al. MK-801 fails to protect against the dopaminergic neuropathology produced by systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice or intranigral 1-methyl-4-phenylpyridinium in rats. J Neurochem 1992; 58(5): 1979–82

    Article  PubMed  CAS  Google Scholar 

  195. Lange KW, Loschmann PA, Sofic E, et al. The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates. Naunyn Schmiedebergs Arch Pharmacol 1993; 348(6): 586–92

    Article  PubMed  CAS  Google Scholar 

  196. Zuddas A, Oberto G, Vaglini F, et al. MK-801 prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in primates. J Neurochem 1992; 59(2): 733–9

    Article  PubMed  CAS  Google Scholar 

  197. Blandini F, Nappi G, Greenamyre JT. Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson’s disease. Ann Neurol 2001; 49(4): 525–9

    Article  PubMed  CAS  Google Scholar 

  198. De Blasi A, Conn PJ, Pin J, et al. Molecular determinants of metabotropic glutamate receptor signaling. Trends Pharmacol Sci 2001; 22(3): 114–20

    Article  PubMed  Google Scholar 

  199. Alagarsamy S, Sorensen SD, Conn PJ. Coordinate regulation of metabotropic glutamate receptors. Curr Opin Neurobiol 2001; 11(3): 357–62

    Article  PubMed  CAS  Google Scholar 

  200. Pisani A, Bernardi G, Bonsi P, et al. Cell-type specificity of mGluR activation in striatal neuronal subtypes. Amino Acids 2000; 19(1): 119–29

    Article  PubMed  CAS  Google Scholar 

  201. Calabresi P, Centonze D, Pisani A, et al. Metabotropic glutamate receptors and cell-type-specific vulnerability in the striatum: implication for ischemia and Huntington’s disease. Exp Neurol 1999; 158(1): 97–108

    Article  PubMed  CAS  Google Scholar 

  202. Sacaan AI, Monn JA, Schoepp DD. Intrastriatal injection of a selective metabotropic excitatory amino acid receptor agonist induces contralateral turning in the rat. J Pharmacol Exp Ther 1991; 259(3): 1366–70

    PubMed  CAS  Google Scholar 

  203. Sacaan AI, Bymaster FP, Schoepp DD. Metabotropic glutamate receptor activation produces extrapyramidal motor system activation that is mediated by striatal dopamine. J Neurochem 1992; 59(1): 245–51

    Article  PubMed  CAS  Google Scholar 

  204. Kearney JA, Frey KA, Albin RL. Metabotropic glutamate agonist-induced rotation: a pharmacological, FOS immunohistochemical, and [14C]-2-deoxyglucose autoradiographic study. J Neurosci 1997; 17(11): 4415–25

    PubMed  CAS  Google Scholar 

  205. Kaatz KW, Albin RL. Intrastriatal and intrasubthalamic stimulation of metabotropic glutamate receptors: a behavioral and Fos immunohistochemical study. Neuroscience 1995; 66(1): 55–65

    Article  PubMed  CAS  Google Scholar 

  206. Calabresi P, Mercuri NB, Bernardi G. Activation of quisqualate metabotropic receptors reduces glutamate and GABA-mediated synaptic potentials in the rat striatum. Neurosci Lett 1992; 139(1): 41–4

    Article  PubMed  CAS  Google Scholar 

  207. East SJ, Hill MP, Brotchie JM. Metabotropic glutamate receptor agonists inhibit endogenous glutamate release from rat striatal synaptosomes. Eur J Pharmacol 1995; 277(1): 117–21

    Article  PubMed  CAS  Google Scholar 

  208. Lovinger DM, McCool BA. Metabotropic glutamate receptormediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. J Neurophysiol 1995; 73(3): 1076–83

    PubMed  CAS  Google Scholar 

  209. Lombardi G, Alesiani M, Leonardi P, et al. Pharmacological characterization of the metabotropic glutamate receptor inhibiting D-[3H]-aspartate output in rat striatum. Br J Pharmacol 1993; 110(4): 1407–12

    Article  PubMed  CAS  Google Scholar 

  210. Pisani A, Calabresi P, Centonze D, et al. Activation of group III metabotropic glutamate receptors depresses glutamatergic transmission at corticostriatal synapse. Neuropharmacology 1997; 36(6): 845–51

    Article  PubMed  CAS  Google Scholar 

  211. Stefani A, Pisani A, Mercuri NB, et al. Activation of metabotropic glutamate receptors inhibits calcium currents and GABA-mediated synaptic potentials in striatal neurons. J Neurosci 1994; 14 (11 Pt 1): 6734–43

    PubMed  CAS  Google Scholar 

  212. Poisik OV, Mannaioni G, Traynelis S, et al. Distinct functional roles of the metabolic glutamate receptors 1 and 5 in the rat globus pallidus. J Neurosci 2003; 23(1): 122–30

    PubMed  Google Scholar 

  213. Beurrier C, Congar P, Bioulac B, et al. Subthalamic nucleus neurons switch from single-spike activity to burst-firing mode. J Neurosci 1999; 19(2): 599–609

    PubMed  CAS  Google Scholar 

  214. Awad-Granko H, Conn PJ. Activation of groups I or III metabotropic glutamate receptors inhibits excitatory transmission in the rat subthalamic nucleus. Neuropharmacology 2001; 41(1): 32–41

    Article  PubMed  CAS  Google Scholar 

  215. Kearney JA, Albin RL. Intrasubthalamic nucleus metabotropic glutamate receptor activation: a behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic study. Neuroscience 2000; 95(2): 409–16

    Article  PubMed  CAS  Google Scholar 

  216. Bradley SR, Marino MJ, Wittmann M, et al. Activation of group II metabotropic glutamate receptors inhibits synaptic excitation of the substantia nigra pars reticulata. J Neurosci 2000; 20(9): 3085–94

    PubMed  CAS  Google Scholar 

  217. Wittmann M, Marino MJ, Bradley SR, et al. Activation of group III mGluRs inhibits GABAergic and glutamatergic transmission in the substantia nigra pars reticulata. J Neurophysiol 2001; 85(5): 1960–8

    PubMed  CAS  Google Scholar 

  218. Marino MJ, Wittman M, Bradley SR, et al. Activation of group I metabotropic glutamate receptors produces a direct excitation and disinhibition of GABAergic projection neurons in the substantia nigra pars reticulata. J Neurosci 2001; 21(18): 7001–12

    PubMed  CAS  Google Scholar 

  219. Hubert GW, Paquet M, Smith Y. Differential subcellular localization of mGluRla and mGluR5 in the rat and monkey substantia nigra. J Neurosci 2001; 21(6): 1838–47

    PubMed  CAS  Google Scholar 

  220. Magill PJ, Bolam JP, Bevan MD. Relationship of activity in the subthalamic nucleus-globus pallidus network to cortical electroencephalogram. J Neurosci 2000; 20(2): 820–33

    PubMed  CAS  Google Scholar 

  221. Spooren WP, Gasparini F, Bergmann R, et al. Effects of the prototypical mGlu (5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. Eur J Pharmacol 2000; 406(3): 403–10

    Article  PubMed  CAS  Google Scholar 

  222. Ossowska K, Konieczny J, Wolfarth S, et al. Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats. Neuropharmacology 2001; 41(4): 413–20

    Article  PubMed  CAS  Google Scholar 

  223. Breysse N, Baunez C, Spooren W, et al. Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J Neurosci 2002; 22(13): 5669–78

    PubMed  CAS  Google Scholar 

  224. Hill MP, McGuire SG, Crossman AR, et al. The mGluR5 receptor antagonist SIB-1830 reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease [abstract]. Soc Neurosci 2001; 25(16): 200

    Google Scholar 

  225. Testa CM, Standaert DG, Young AB, et al. Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat. J Neurosci 1994; 14 (5 Pt 2): 3005–18

    PubMed  CAS  Google Scholar 

  226. Konieczny J, Ossowska K, Wolfarth S, et al. LY354740, a group II metabotropic glutamate receptor agonist with potential antiparkinsonian properties in rats. Naunyn Schmiedebergs Arch Pharmacol 1998; 358(4): 500–2

    Article  PubMed  CAS  Google Scholar 

  227. Dawson L, Chadha A, Megalou M, et al. The group II metabotropic glutamate receptor agonist, DCG-IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine-treated rat. Br J Pharmacol 2000; 129(3): 541–6

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Dr Valenti would like to acknowledge and thank the Post-doctoral Program in Preclinical and Clinical Pharmacology, University of Catania, Italy. The authors are employed by Merck and Co. Inc. There are no conflicts of interest associated with the content of this review.

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  1. Department of Neuroscience, Merck Research Laboratories, Merck & Co., Inc, 770 Sumneytown Pike, PO Box 4, West Point, WP 46-300, Pennsylvania, 19486-0004, USA

    Michael J. Marino, Ornella Valenti &  P. Jeffrey Conn

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Marino, M.J., Valenti, O. & Conn, P.J. Glutamate Receptors and Parkinson’s Disease. Drugs Aging 20, 377–397 (2003). https://doi.org/10.2165/00002512-200320050-00006

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