Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease
Abstract
The development of dyskinesias and other motor complications greatly limits the use of levodopa therapy in Parkinson's disease (PD). Studies in rodent models of PD suggest that an important mechanism underlying the development of levodopa-related motor complications is alterations in striatal NMDA receptor function. We examined striatal NMDA receptors in the MPTP-lesioned primate model of PD. Quantitative immunoblotting was used to determine the subcellular abundance of NR1, NR2A and NR2B subunits in striata from unlesioned, MPTP-lesioned (parkinsonian) and MPTP-lesioned, levodopa-treated (dyskinetic) macaques. In parkinsonian macaques, NR1 and NR2B subunits in synaptosomal membranes were decreased to 66 +/- 11% and 51.2 +/- 5% of unlesioned levels respectively, while the abundance of NR2A was unaltered. Levodopa treatment eliciting dyskinesia normalized NR1 and NR2B and increased NR2A subunits to 150 +/- 12% of unlesioned levels. No alterations in receptor subunit tyrosine phosphorylation were detected. These results demonstrate that altered synaptic abundance of NMDA receptors with relative enhancement in the abundance of NR2A occurs in primate as well as rodent models of parkinsonism, and that in the macaque model, NR2A subunit abundance is further increased in dyskinesia. These data support the view that alterations in striatal NMDA receptor systems are responsible for adaptive and maladaptive responses to dopamine depletion and replacement in parkinsonism, and highlight the value of subtype selective NMDA antagonists as novel therapeutic approaches for PD.
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NMDA-receptor antagonists such as MK801, ketamine, and phencyclidine cause symptoms similar to anti-NMDA-receptor encephalitis, including psychotic behaviour, signs of involvement of dopaminergic pathways, and autonomic dysfunction.
“Consistent with this antibody-induced decrease in the numbers of NMDA receptors, several NMDA-receptor antagonists such as MK801, ketamine, and phencyclidine cause symptoms similar to anti-NMDA-receptor encephalitis, including psychotic behaviour,21,22 signs of involvement of dopaminergic pathways (rigidity, dystonia, orofacial movements, tremor)22–25 and autonomic dysfunction (cardiac dysrhythmia”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [25]
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- Authors
- Hallett, P. J., Dunah, A. W., Ravenscroft, P., Zhou, S., Bezard, E., Crossman, A. R., Brotchie, J. M., & Standaert, D. G.
- Affiliations
- Harvard University (US)
- University of Manchester (GB)
- Toronto Western Hospital (CA)
- Corresponding author
- Hallett, P.J.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 48
- Issue
- 4
- Pages
- 503-516
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2053473574
- Cited by
- 192
- References
- 47
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 13 · 2017: 6 · 2016: 9 · 2015: 8 · 2014: 15 · 2013: 15 · 2012: 13
- FWCI
- 9.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Bedfordshire Repository (University of Bedfordshire) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS34361)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Parkinson's disease, dyskinesia, NMDA receptor subunits, striatum, MPTP lesion, macaque, levodopa, NR2A, NR2B, NR1, dopamine depletion, NMDA receptor antagonists, motor complications
- MeSH terms
- Animals, Corpus Striatum, Female, Macaca mulatta, Receptors, N-Methyl-D-Aspartate, MPTP Poisoning, Dyskinesias
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