Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment

Dopamine D-2 receptors are the main target of antipsychotic drugs. In the brain, D-2 receptors coexpress with adenosine A(2A) and CB1 cannabinoid receptors, leading to functional interactions. The protein and messenger RNA (mRNA) contents of A(2A), D-2, and CB1 receptors were quantified in postmortem prefrontal cortex of subjects with schizophrenia. The study was performed in subjects suffering schizophrenia (n = 31) who mainly died by suicide, matched with non-schizophrenia suicide victims (n = 13) and non-suicide controls (n = 33). The density of receptor proteins was evaluated by immunodetection techniques, and their relative mRNA expression was quantified by quantitative real-time polymerase chain reaction. In schizophrenia, the densities of A(2A) (90 +/- 6%, n = 24) and D-2-like receptors (95 +/- 5%, n = 22) did not differ from those in controls (100%). Antipsychotic treatment did not induce changes in the protein expression. In contrast, the immunodensity of CB1 receptors was significantly decreased (71 +/- 7%, n = 11; p < 0.05) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104 +/- 13%, n = 11). The relative mRNA amounts encoding for A(2A), D-2, and CB1 receptors were similar in brains of drug-free, antipsychotic-treated subjects with schizophrenia and controls. The findings suggest that antipsychotics induce down-regulation of CB1 receptors in brain. Since A(2A), D-2, and CB1 receptors coexpress on brain GABAergic neurons and reductions in markers of GABA neurotransmission have been identified in schizophrenia, a lower density of CB1 receptor induced by antipsychotics could represent an adaptative mechanism that reduces the endocannabinoid-mediated suppression of GABA release, contributing to the normalization of cognitive functions in the disorder.