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 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.
Guigoni
Céline
C
CNRS UMR 5227, Université Victor Segalen-Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
Doudnikoff
Evelyne
E
Li
Qin
Q
Bloch
Bertrand
B
Bezard
Erwan
E
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D002451:Cell Compartmentation / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D008252:Macaca fascicularis; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology; D021381:Protein Transport; D011940:Receptor Aggregation / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000978:Antiparkinson Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D004298:Dopamine