Subregional reduction in CB1 receptor in dopamine neurons in postmortem schizophrenia midbrain

Schizophrenia is a chronic psychiatric disorder affecting 1% of the population. Common treatment strategies include antipsychotics that block or modulate dopamine receptors. However, ∼34% of patients exhibit resistance to current antipsychotic medications targeting dopaminergic receptors, which are central to the pathophysiology of psychosis. Consequently, research has focused on alternative modulators of dopamine signaling. The cannabinoid receptor 1 (CB1) has the potential to neuromodulate neurons. CB1 expression in dopamine neurons and reactive GFAP+ astrocytes is altered in schizophrenia. Here, we examined CB1 expressions in dopamine neurons and reactive GFAP+ astrocytes using immunofluorescent staining in post-mortem human midbrain tissue from individuals with schizophrenia (n = 9) and matched controls (n = 10). As previously established, within the substantia nigra we report no change in dopamine neurons and increased number of astrocytes. No changes were found in the ventral tegmental area (VTA). Upon subregional analysis of the substantia nigra, there was decreased CB1 expression on dopamine neurons in the medial and ventral subregions of the substantia nigra. Notably, astrocyte density increased specifically in the dorsal subregion, with no change in astrocytic CB1. These findings demonstrate subregional differences within the midbrain, with no change in the VTA, and that the substantia nigra undergoes the prominent molecular changes in Schizophrenia. Overall, it provides insight into the spatial molecular pathology of the midbrain in schizophrenia.