Pharmacological Analysis Demonstrates Dramatic Alteration of D1Dopamine Receptor Neuronal Distribution in the Rat Analog of l-DOPA-Induced Dyskinesia

Abstract

We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a rat analog of l-DOPA-induced dyskinesia to understand whether alterations in dopamine receptor fate in striatal neurons may be involved in mechanisms leading to movement abnormalities. Detailed analysis at the ultrastructural level demonstrates specific alterations of dopamine D(1) receptor (D(1)R) subcellular localization in striatal medium spiny neurons in l-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary movements (AIMs). This includes exaggerated D(1)R expression at the plasma membrane. However, D(1)R retains ability of internalization, as a challenge with the potent D(1)R agonist SKF-82958 induces a strong decrease of labeling at membrane in animals with AIMs. Since a functional cross talk between D(1)R and D(3)R has been suggested, we hypothesized that their coactivation by dopamine derived from l-DOPA might anchor D(1)R at the membrane. Accordingly, cotreatment with l-DOPA and the D(3)R antagonist ST 198 restores normal level of membrane-bound D(1)R. Together, these results demonstrate that AIMs are related to abnormal D(1)R localization at the membrane and intraneuronal trafficking dysregulation, and suggest that strategies aiming at disrupting the D(1)R-D(3)R cross talk might reduce l-DOPA-induced dyskinesia by reducing D(1)R availability at the membrane.