Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease.
Neuropharmacology. 2005-03-01; 48(4): 503-516
DOI: 10.1016/j.neuropharm.2004.11.008
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1. Neuropharmacology. 2005 Mar;48(4):503-16.
Alterations of striatal NMDA receptor subunits associated with the development of
dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease.
Hallett PJ(1), Dunah AW, Ravenscroft P, Zhou S, Bezard E, Crossman AR, Brotchie
JM, Standaert DG.
Author information:
(1)MassGeneral Institute for Neurodegenerative Disease, Massachusetts General
Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
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.
DOI: 10.1016/j.neuropharm.2004.11.008
PMID: 15755478 [Indexed for MEDLINE]