We have associated behavioral, pharmacological, and quantitative immunohistochemical study in a rat analog ofl-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 D₁receptor (D₁R) subcellular localization in striatal medium spiny neurons inl-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 froml-DOPA might anchor D₁R at the membrane. Accordingly, cotreatment withl-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 reducel-DOPA-induced dyskinesia by reducing D₁R availability at the membrane.