RT Journal Article
SR Electronic
T1 Loss of Synaptic D1 Dopamine/<em>N</em>-Methyl-<span class="sc">d</span>-aspartate Glutamate Receptor Complexes in <span class="sc">l</span>-DOPA-Induced Dyskinesia in the Rat
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 805
OP 812
DO 10.1124/mol.105.016667
VO 69
IS 3
A1 Chiara Fiorentini
A1 Maria Cristina Rizzetti
A1 Chiara Busi
A1 Sandra Bontempi
A1 Ginetta Collo
A1 PierFranco Spano
A1 Cristina Missale
YR 2006
UL http://molpharm.aspetjournals.org/content/69/3/805.abstract
AB Glutamate-mediated mechanisms are related to the motor complications of l-DOPA therapy in Parkinson's disease (PD). In striatal postsynaptic densities (PSD), the dopamine D1 receptor (D1R) is part of an oligomeric complex with the glutamate N-methyl-d-aspartate receptor (NMDAR), determining the strength of corticostriatal transmission. We studied D1R/NMDAR complex alterations induced by l-DOPA in the 6-hydroxydopamine-lesioned rat model of PD. l-DOPA-treated hemiparkinsonian rats were determined to be dyskinetic or nondyskinetic based on behavioral testing. D1R/NMDAR assemblies containing NR1-C2 and NR2B subunits were decreased in the PSD of lesioned striatum. Short-term l-DOPA administration improved akinesia and restored the synaptic abundance of D1R, NR1-C2 and NR2B. Prolonged l-DOPA treatment also normalized synaptic D1R/NMDAR complexes in nondyskinetic rats, but remarkably reduced them in the dyskinetic group without changing their interaction. This decrease involved NR1-C2, NR1-C2′, NR2A, and NR2B subunits. The composition of residual synaptic D1R/NMDAR complexes in dyskinetic rats may thus be different from that observed in lesioned rats, suggesting that expression of different motor dysfunctions might be related to the receptor profile at corticostriatal synapses. The levels of D1R/NMDAR complexes were unchanged in total striatal membrane proteins, suggesting that the decrease of these species in the PSD is likely to reflect an altered receptor trafficking. In human embryonic kidney 293 cells expressing the D1R/NMDAR, complex costimulation of both D1R and NMDAR, but not individual receptor activation, promoted internalization, suggesting that development of dyskinesias might be related to agonist-mediated down-regulation of the D1R/NMDAR complex at corticostriatal synapses.