Previous studies suggest that the endocannabinoid system plays an important role in the neuropathological basis of Parkinson's disease (PD). This study was designed to detect potential alterations in the cannabinoid receptors CB1 (CB(1)r) and CB2 (A isoform, CB(2A)r), and in monoacylglycerol lipase (MAGL) gene expression in the substantia nigra (SN) and putamen (PUT) of patients with PD. Immunohistochemical studies were performed to identify precise CB(2)r cellular localization in the SN of control and PD patients. To ensure the validity and reliability of gene expression data, the RNA integrity number (RIN) was calculated. CB(1)r, CB(2A)r, and MAGL gene expressions were evaluated by real-time polymerase chain reaction (real-time PCR) using Taqman assays. Immunohistochemical experiments with in situ proximity ligation assay (PLA) were used to detect the precise cellular localization of CB(2)r in neurons, astrocytes, and/or microglia. All RIN values from control and PD postmortem brain samples were > 6. CB(1)r gene expression was unchanged in the SN but significantly higher in the PUT of patients with PD. CB(2A)r gene expression was significantly increased (4-fold) in the SN but decreased in the PUT, whereas MAGL gene expression was decreased in the SN and increased in the PUT. Immunohistochemical analyses revealed that CB(2)r co-localize with astrocytes but not with neurons or microglial cells in the SN. The results of the present study suggest that CB(1)r, CB(2)r, and MAGL are closely related to the neuropathological processes of PD. Therefore, the pharmacological modulation of these targets could represent a new potential therapeutic tool for the management of PD.