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

Abstract

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 D1 receptor-mediated transmission, we also questioned the possible role of subcellular localization of D1 and D2 receptors in mediating these effects as we previously showed that D1 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 D1 and D2 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 D1 receptor at the plasma membrane of striatal neurons in the parkinsonian animals and a strong increase of D1 expression both at the membrane and in cytoplasm of dyskinetic animals, whereas D2 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 D1 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 D1 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.

Keywords

• Dopamine receptor
• Electron microscopy
• Immunohistochemistry
• Subcellular distribution