Parkinson's disease (PD) is a dopaminergic-related pathology in which functioning of the basal ganglia is altered. It has been postulated that a direct receptor-receptor interaction - i.e. of dopamine D-2 receptor (D2R) with adenosine A(2A) receptor (A(2A)R) (forming D2R-A(2A)R oligomers) - finely regulates this brain area. Accordingly, elucidating whether the pathology prompts changes to these complexes could provide valuable information for the design of new PD therapies. Here, we first resolved a long-standing question concerning whether D2R-A(2A)R assembly occurs in native tissue: by means of different complementary experimental approaches (i.e. immunoelectron microscopy, proximity ligation assay and TR-FRET), we unambiguously identified native D2R-A(2A)R oligomers in rat striatum. Subsequently, we determined that, under pathological conditions (i.e. in a rat PD model), D2R-A(2A)R interaction was impaired. Collectively, these results provide definitive evidence for alteration of native D2R-A(2A)R oligomers in experimental parkinsonism, thus conferring the rationale for appropriate oligomer-based PD treatments.