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 (D 2R) with adenosine A 2A receptor (A 2AR) (forming D 2R-A 2AR 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 D 2R-A 2AR 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 D 2R-A 2AR oligomers in rat striatum. Subsequently, we determined that, under pathological conditions (i.e. in a rat PD model), D 2R-A 2AR interaction was impaired. Collectively, these results provide definitive evidence for alteration of native D 2R-A 2AR oligomers in experimental parkinsonism, thus conferring the rationale for appropriate oligomer-based PD treatments.