Skip to main content
SpringerLink
Log in

Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline, CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

This study assessed striatal N-methyl-D-aspartate (NMDA) glutamate receptors of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with levodopa (L-DOPA)-induced dyskinesias (LID). In a first experiment, four MPTP monkeys receiving L-DOPA/Benserazide alone developed dyskinesias. Four MPTP monkeys received L-DOPA/Benserazide plus CI-1041 an NMDA antagonist selective for NR1/NR2B and four were treated with L-DOPA/Benserazide plus a small dose of cabergoline; one monkey of each group developed mild dyskinesias at the end of treatment. In a second experiment, a kynurenine 3-hydroxylase inhibitor Ro 61-8048, combined with L-DOPA/Benserazide, reduced dyskinesias in MPTP monkeys. Drug-treated MPTP monkeys were compared to intact monkeys and saline-treated MPTP monkeys. Glutamate receptors were investigated by autoradiography using [3H]CGP-39653 (NR1/NR2A antagonist) and [3H]Ro25-6981 (NR1/NR2B antagonist). In general, striatal [3H]CGP-39653 specific binding was unaltered in all experimental groups. MPTP lesion decreased striatal [3H]Ro25-6981 specific binding; these levels were enhanced in the L-DOPA-alone-treated MPTP monkeys and decreased in antidyskinetic drugs treated monkeys. Maximal dyskinesias scores of the MPTP monkeys correlated significantly with [3H]Ro25-6981 specific binding in the rostral and caudal striatum. Hence, MPTP lesion, L-DOPA treatment and prevention of LID with CI-1041 and cabergoline, or reduction with Ro 61-8048 were associated with modulation of NR2B/NMDA glutamate receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

DA:

Dopamine

DAT:

Dopamine Transporter

DOPAC:

3, 4 dihydroxyphenylacetic acid

HVA:

Homovanillic acid

L-DOPA:

Levodopa

LID:

L-DOPA-induced dyskinesias

LTD:

long term depression

LTP:

long term potentiation

3-MT:

3-methoxytyramine

NMDA:

N-methyl-D-aspartate

PD:

Parkinson’s disease

References

  • Bara-Jimenez, W., Dimitrova, T. D., Sherzai, A., Aksu, M., & Chase, T. N. (2006). Glutamate release inhibition ineffective in levodopa-induced motor complications. Movement Disorders, 21, 1380–1383. doi:10.1002/mds.20976.

    Article  PubMed  Google Scholar 

  • Barria, A., & Malinow, R. (2002). Subunit-specific NMDA receptor trafficking to synapses. Neuron, 35, 345–353. doi:10.1016/S0896-6273(02)00776-6.

    Article  PubMed  CAS  Google Scholar 

  • Belanger, N., Gregoire, L., Hadj Tahar, A., & Bedard, P. J. (2003). Chronic treatment with small doses of cabergoline prevents dopa-induced dyskinesias in parkinsonian monkeys. Movement Disorders, 18, 1436–1441. doi:10.1002/mds.10589.

    Article  PubMed  Google Scholar 

  • Blanchet, P. J., Calon, F., Morissette, M., et al. (2004). Relevance of the MPTP primate model in the study of dyskinesia priming mechanisms. Parkinsonism & Related Disorders, 10, 297–304. doi:10.1016/j.parkreldis.2004.02.011.

    Article  Google Scholar 

  • Bliss, T., & Schoepfer, R. (2004). Neuroscience. Controlling the ups and downs of synaptic strength. Science, 304, 973–974. doi:10.1126/science.1098805.

    Article  PubMed  CAS  Google Scholar 

  • Brotchie, J. M., Lee, J., & Venderova, K. (2005). Levodopa-induced dyskinesia in Parkinson’s disease. Journal of Neural Transmission, 112, 359–391. doi:10.1007/s00702-004-0251-7.

    Article  PubMed  CAS  Google Scholar 

  • Calabresi, P., Picconi, B., Parnetti, L., & Di Filippo, M. (2006). A convergent model for cognitive dysfunctions in Parkinson’s disease: the critical dopamine-acetylcholine synaptic balance. The Lancet Neurology, 5, 974–983. doi:10.1016/S1474-4422(06)70600-7.

    Article  CAS  Google Scholar 

  • Calon, F., Morissette, M., Ghribi, O., et al. (2002). Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 26, 127–138. doi:10.1016/S0278-5846(01)00237-8.

    Article  CAS  Google Scholar 

  • Calon, F., Rajput, A. H., Hornykiewicz, O., Bedard, P. J., & Di Paolo, T. (2003). Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson’s disease. Neurobiology of Disease, 14, 404–416. doi:10.1016/j.nbd.2003.07.003.

    Article  PubMed  CAS  Google Scholar 

  • Cepeda, C., Buchwald, N. A., & Levine, M. S. (1993). Neuromodulatory actions of dopamine in the neostriatum are dependent upon the excitatory amino acid receptor subtypes activated. Proceedings of the National Academy of Sciences of the United States of America, 90, 9576–9580. doi:10.1073/pnas.90.20.9576.

    Article  PubMed  CAS  Google Scholar 

  • Chase, T. N. (2004). Striatal plasticity and extrapyramidal motor dysfunction. Parkinsonism & Related Disorders, 10, 305–313. doi:10.1016/j.parkreldis.2004.02.012.

    Article  Google Scholar 

  • Chen, L. R., Wesley, J. A., Bhattachar, S., Ruiz, B., Bahash, K., & Babu, S. R. (2003). Dissolution behavior of a poorly water soluble compound in the presence of Tween 80. Pharmaceutical Research, 20, 797–801. doi:10.1023/A:1023493821302.

    Article  PubMed  CAS  Google Scholar 

  • Desce, J. M., Godeheu, G., Galli, T., et al. (1992). L-glutamate-evoked release of dopamine from synaptosomes of the rat striatum: involvement of AMPA and N-methyl-D-aspartate receptors. Neuroscience, 47, 333–339. doi:10.1016/0306-4522(92)90249-2.

    Article  PubMed  CAS  Google Scholar 

  • Deutch, A. Y. (1993). Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson’s disease. Journal of Neural Transmission, 91, 197–221. doi:10.1007/BF01245232.

    Article  PubMed  CAS  Google Scholar 

  • Dunah, A. W., Wang, Y., Yasuda, R. P., et al. (2000). 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. Molecular Pharmacology, 57, 342–352.

    PubMed  CAS  Google Scholar 

  • Erreger, K., Chen, P. E., Wyllie, D. J., & Traynelis, S. F. (2004). Glutamate receptor gating. Critical Reviews in Neurobiology, 16, 187–224. doi:10.1615/CritRevNeurobiol.v16.i3.10.

    Article  PubMed  CAS  Google Scholar 

  • Erreger, K., Dravid, S. M., Banke, T. G., Wyllie, D. J., & Traynelis, S. F. (2005). Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. The Journal of Physiology, 563, 345–358. doi:10.1113/jphysiol.2004.080028.

    Article  PubMed  CAS  Google Scholar 

  • Erreger, K., Geballe, M. T., Kristensen, A., et al. (2007). Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. Molecular Pharmacology, 72, 907–920. doi:10.1124/mol.107.037333.

    Article  PubMed  CAS  Google Scholar 

  • Gerkin, R. C., Lau, P. M., Nauen, D. W., Wang, Y. T., & Bi, G. Q. (2007). Modular competition driven by NMDA receptor subtypes in spike-timing-dependent plasticity. Journal of Neurophysiology, 97, 2851–2862. doi:10.1152/jn.00860.2006.

    Article  PubMed  CAS  Google Scholar 

  • Gilgun-Sherki, Y., Melamed, E., Ziv, I., & Offen, D. (2003). Riluzole, an inhibitor of glutamatergic transmission, suppresses levodopa-induced rotations in 6-hydroxydopamine-lesioned rats. Pharmacology & Toxicology, 93, 54–56. doi:10.1034/j.1600-0773.2003.930108.x.

    Article  CAS  Google Scholar 

  • Gregoire, L., Rassoulpour, A., Guidetti, P., et al. (2008). Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behavioural Brain Research, 186, 161–167. doi:10.1016/j.bbr.2007.08.007.

    Article  PubMed  CAS  Google Scholar 

  • Groc, L., Choquet, D., Stephenson, F. A., et al. (2007). NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. The Journal of Neuroscience, 27, 10165–10175. doi:10.1523/JNEUROSCI.1772-07.2007.

    Article  PubMed  CAS  Google Scholar 

  • Hadj Tahar, A., Gregoire, L., Darre, A., et al. (2004). Effect of a selective glutamate antagonist on L-dopa-induced dyskinesias in drug-naive parkinsonian monkeys. Neurobiology of Disease, 15, 171–176. doi:10.1016/j.nbd.2003.10.007.

    Article  PubMed  CAS  Google Scholar 

  • Hallett, P. J., Dunah, A. W., Ravenscroft, P., et al. (2005). Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Neuropharmacology, 48, 503–516. doi:10.1016/j.neuropharm.2004.11.008.

    Article  PubMed  CAS  Google Scholar 

  • He, L., Di Monte, D. A., Langston, J. W., & Quik, M. (2000). Autoradiographic analysis of N-methyl-D-aspartate receptor binding in monkey brain: effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and levodopa treatment. Neuroscience, 99, 697–704. doi:10.1016/S0306-4522(00)00235-9.

    Article  PubMed  CAS  Google Scholar 

  • Hilmas, C., Pereira, E. F., Alkondon, M., et al. (2001). The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. The Journal of Neuroscience, 21, 7463–7473.

    PubMed  CAS  Google Scholar 

  • Hurley, M. J., Jackson, M. J., Smith, L. A., Rose, S., & Jenner, P. (2005). Immunoautoradiographic analysis of NMDA receptor subunits and associated postsynaptic density proteins in the brain of dyskinetic MPTP-treated common marmosets. The European Journal of Neuroscience, 21, 3240–3250. doi:10.1111/j.1460-9568.2005.04169.x.

    Article  PubMed  CAS  Google Scholar 

  • Lavezzari, G., McCallum, J., Dewey, C. M., & Roche, K. W. (2004). Subunit-specific regulation of NMDA receptor endocytosis. The Journal of Neuroscience, 24, 6383–6391. doi:10.1523/JNEUROSCI.1890-04.2004.

    Article  PubMed  CAS  Google Scholar 

  • Maura, G., Carbone, R., & Raiteri, M. (1989). Aspartate-releasing nerve terminals in rat striatum possess D-2 dopamine receptors mediating inhibition of release. The Journal of Pharmacology and Experimental Therapeutics, 251, 1142–1146.

    PubMed  CAS  Google Scholar 

  • Morissette, M., Dridi, M., Calon, F., et al. (2006). Prevention of levodopa-induced dyskinesias by a selective NR1A/2B N-methyl-D-aspartate receptor antagonist in parkinsonian monkeys: implication of preproenkephalin. Movement Disorders, 21, 9–17. doi:10.1002/mds.20654.

    Article  PubMed  Google Scholar 

  • Moroni, F., Cozzi, A., Carpendo, R., et al. (2005). Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus. Neuropharmacology, 48, 788–795. doi:10.1016/j.neuropharm.2004.10.019.

    Article  PubMed  CAS  Google Scholar 

  • Nemeth, H., Toldi, J., & Vecsei, L. (2005). Role of kynurenines in the central and peripheral nervous systems. Current Neurovascular Research, 2, 249–260. doi:10.2174/1567202054368326.

    Article  PubMed  Google Scholar 

  • Picconi, B., Centonze, D., Hakansson, K., et al. (2003). Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nature Neuroscience, 6, 501–506.

    PubMed  CAS  Google Scholar 

  • Picconi, B., Pisani, A., Barone, I., et al. (2005). Pathological synaptic plasticity in the striatum: implications for Parkinson’s disease. Neurotoxicology, 26, 779–783. doi:10.1016/j.neuro.2005.02.002.

    Article  PubMed  CAS  Google Scholar 

  • Samadi, P., Gregoire, L., Morissette, M., et al. (2008). mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys. Neurobiology of Aging, 29, 1040–1051. doi:10.1016/j.neurobiolaging.2007.02.005.

    Article  PubMed  CAS  Google Scholar 

  • Samadi, P., Gregoire, L., Rassoulpour, A., et al. (2005). Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys. Movement Disorders, 20, 792–802. doi:10.1002/mds.20596.

    Article  PubMed  Google Scholar 

  • Samuel, D., Errami, M., & Nieoullon, A. (1990). Localization of N-methyl-D-aspartate receptors in the rat striatum: effects of specific lesions on the [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding. Journal of Neurochemistry, 54, 1926–1933. doi:10.1111/j.1471-4159.1990.tb04893.x.

    Article  PubMed  CAS  Google Scholar 

  • Schwab, R. S., England, A. C., Jr., Poskanzer, D. C., & Young, R. R. (1969). Amantadine in the treatment of Parkinson’s disease. Journal of the American Medical Association, 208, 1168–1170. doi:10.1001/jama.208.7.1168.

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz, R., & Pellicciari, R. (2002). Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. The Journal of Pharmacology and Experimental Therapeutics, 303, 1–10. doi:10.1124/jpet.102.034439.

    Article  PubMed  CAS  Google Scholar 

  • Stone, T. W. (2000). Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends in Pharmacological Sciences, 21, 149–154. doi:10.1016/S0165-6147(00)01451-6.

    Article  PubMed  CAS  Google Scholar 

  • Szabo, J., & Cowan, W. M. (1984). A stereotaxic atlas of the brain of the cynomolgus monkey (Macaca fascicularis). The Journal of Comparative Neurology, 222, 265–300. doi:10.1002/cne.902220208.

    Article  PubMed  CAS  Google Scholar 

  • Thanvi, B., Lo, N., & Robinson, T. (2007). Levodopa-induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgraduate Medical Journal, 83, 384–388. doi:10.1136/pgmj.2006.054759.

    Article  PubMed  CAS  Google Scholar 

  • Tovar, K. R., & Westbrook, G. L. (2002). Mobile NMDA receptors at hippocampal synapses. Neuron, 34, 255–264. doi:10.1016/S0896-6273(02)00658-X.

    Article  PubMed  CAS  Google Scholar 

  • Ulas, J., Weihmuller, F. B., Brunner, L. C., et al. (1994). Selective increase of NMDA-sensitive glutamate binding in the striatum of Parkinson’s disease, Alzheimer’s disease, and mixed Parkinson’s disease/Alzheimer’s disease patients: an autoradiographic study. The Journal of Neuroscience, 14, 6317–6324.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was funded by a grant from the Canadian Institutes of Health Research to TDP. BO was supported by the Government of Ivory Coast and SB by the Government of Tunisia.

Author information

Authors and Affiliations

  1. Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, 2705 Laurier Blvd, Quebec, QC, G1V 4G2, Canada

    Bazoumana Ouattara, Samah Belkhir, Marc Morissette, Mehdi Dridi, Pershia Samadi, Laurent Grégoire & Thérèse Di Paolo

  2. Faculty of Pharmacy, Laval University, Quebec, QC, Canada

    Bazoumana Ouattara, Samah Belkhir, Marc Morissette, Mehdi Dridi, Pershia Samadi, Laurent Grégoire & Thérèse Di Paolo

  3. Global Research & Development, Pfizer, Ann Arbor, MI, USA

    Leonard T. Meltzer

Authors
  1. Bazoumana Ouattara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samah Belkhir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Morissette
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mehdi Dridi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pershia Samadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laurent Grégoire
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leonard T. Meltzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thérèse Di Paolo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thérèse Di Paolo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ouattara, B., Belkhir, S., Morissette, M. et al. Implication of NMDA Receptors in the Antidyskinetic Activity of Cabergoline, CI-1041, and Ro 61-8048 in MPTP Monkeys with Levodopa-induced Dyskinesias. J Mol Neurosci 38, 128–142 (2009). https://doi.org/10.1007/s12031-008-9137-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-008-9137-8

Keywords

Search

Navigation