Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. One of the hallmarks of PD is the alteration in the expression and function of NMDA receptor (NMDAR) and cannabinoid receptor 1 (CB1R). The presence of CB1R-NMDAR complexes has been described in neuronal primary cultures, where the activation of CB1R was suggested to counteract the detrimental NMDAR overactivation in an AD mice model. Thus, we aimed to explore the role of this receptor complex in PD. By using BRET assay, it was demonstrated that a-synuclein induces a reorganization of CB1R-NMDAR complex in transfected HEK-293T cells. Moreover, a-synuclein treatment induced a decrease in the cAMP and MAPK signaling of both CB1R and NMDAR not only in transfected cells but also in neuronal primary cultures. It was also observed that the expression of CB1R-NMDAR complexes was decreased in neurons upon a-synuclein treatment by Proximity Ligation Assay (PLA). Finally, the interaction between CB1R and NMDAR was also studied by PLA in striatal sections of a rat PD model consisting of nigrostriatal lesion with 6-OH-DA. A decrease in the CB1R-NMDAR complex expression was observed in the striatum of lesioned animals and in those rats treated with levodopa and showing dyskinesia, but not in those rats not showing dyskinesia. These results point to a role of CB1R-NMDAR complexes as a new therapeutic target in Parkinson’s disease.