Abstract

Parkinson’s disease (PD) is a dopaminergic-related pathology in which basal ganglia functioning are altered. It has been postulated that a direct receptor-receptor – i.e. dopamine D₂ receptor (D₂R) and adenosine A_2A receptor (A_2AR) – interaction may be finely regulating this brain area. Accordingly, elucidating whether the pathology prompts changes on these structures could grant valuable information for the design of new PD therapies. Here, we first resolved a long-standing question concerning D₂R-A_2AR assembly in native tissue. Thus, by means of different complementary experimental approaches (i.e. immunoelectron microscopy, proximity ligation assay and TR-FRET), we unambiguously identified native D₂R/A_2AR oligomers in rat striatum. Subsequently, we determined that under pathological conditions (i.e. in a rat PD model) D₂R-A_2AR interaction was impaired. Collectively, these results provide definitive evidence for a native D₂R/A_2AR oligomer alteration in experimental parkinsonism, thus conferring the rationale for appropriate oligomer-based PD treatments.