Pharmacological Analysis Demonstrates Dramatic Alteration of D1 Dopamine Receptor Neuronal Distribution in the Rat Analog of L-DOPA-Induced Dyskinesia

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 (D1R) subcellular localization in striatal medium spiny neurons in L-DOPA-treated 6-hydroxydopamine-lesioned rats with abnormal involuntary movements (AIMs). This includes exaggerated D1R expression at the plasma membrane. However, D1R retains ability of internalization, as a challenge with the potent D1R agonist SKF-82958 induces a strong decrease of labeling at membrane in animals with AIMs. Since a functional cross talk between D1R and D3R has been suggested, we hypothesized that their coactivation by dopamine derived from L-DOPA might anchor D1R at the membrane. Accordingly, cotreatment with L-DOPA and the D3R antagonist ST 198 restores normal level of membrane-bound D1R. Together, these results demonstrate that AIMs are related to abnormal D1R localization at the membrane and intraneuronal trafficking dysregulation, and suggest that strategies aiming at disrupting the D1R-D3R cross talk might reduce L-DOPA-induced dyskinesia by reducing D1R availability at the membrane.