Altered D 1 dopamine receptor trafficking in parkinsonian and dyskinetic non-human primates

Dyskinesias represent a debilitating complication of levodopa therapy for Parkinson's disease (PD). While we recently demonstrated that levodopa-induced dyskinesia results from increased dopamine D 1 receptor-mediated transmission, we also questioned the possible role of subcellular localizatio...

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Bibliographic Details
Published in:Neurobiology of disease Vol. 26; no. 2; pp. 452 - 463
Main Authors: Guigoni, Céline, Doudnikoff, Evelyne, Li, Qin, Bloch, Bertrand, Bezard, Erwan
Format: Journal Article
Language:English
Published: Elsevier Inc 2007
Subjects:
Dopamine receptor
Electron microscopy
Immunohistochemistry
Subcellular distribution
Immunohistochemistry
GRK
LM
D 1R
RT
HRP
IgG
l-dopa
6-OHDA
BSA
NHP
Subcellular distribution
PBS
D 2R
TSA
DAB
Dopamine receptor
LID
EM
Electron microscopy
ER
PD
Mb
MPTP
NGS
DA
RER
ISSN:0969-9961, 1095-953X
Online Access:Get full text
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Summary:Dyskinesias represent a debilitating complication of levodopa therapy for Parkinson's disease (PD). While we recently demonstrated that levodopa-induced dyskinesia results from increased dopamine D 1 receptor-mediated transmission, we also questioned the possible role of subcellular localization of D 1 and D 2 receptors in mediating these effects as we previously showed that D 1 receptors undergo differential trafficking in striatal neurons of non-dyskinetic PD patients. Taking advantage of a monkey brain bank, we here report changes affecting the cellular and subcellular distribution of D 1 and D 2 dopamine receptors within the striatum of three experimental groups: normal, parkinsonian and dyskinetic l-dopa-treated parkinsonian animals. Our studies at both light and electron microscopy levels show a recruitment of D 1 receptor at the plasma membrane of striatal neurons in the parkinsonian animals and a strong increase of D 1 expression both at the membrane and in cytoplasm of dyskinetic animals, whereas D 2 receptor distribution is only modestly affected in all conditions. Our results rule out the hypothesis of a pathological overinternalization of dopamine receptors in levodopa-induced dyskinesia but raise the possibility for involvement of D 1 receptors in the priming phenomenon through massive and sudden internalization in response to the first ever administration of l-dopa and for an altered homologous desensitization mechanism in dyskinesia leading to an increased availability of D 1 receptors at membrane. Further experiments including parkinsonian monkeys chronically treated with l-dopa that show no dyskinesia and parkinsonian monkeys treated only once with l-dopa are now necessary to confirm our hypothesis.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2007.02.001