Altered D1 dopamine receptor trafficking in parkinsonian and dyskinetic non-human primates

Dyskinesias represent a debilitating complication of levodopa therapy for Parkinson's disease (PD). While vie 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. (c) 2007 Elsevier Inc. All rights reserved.