α_2A- and α_2C-adrenoceptor expression and functionality in postmortem prefrontal cortex of schizophrenia subjects

Previous evidence suggests that α₂-adrenoceptors (α₂-AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α₂-AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate α_2A-AR and α_2C-AR expression in different subcellular fractions of prefrontal cortex postmortem tissue from antipsychotic-free (absence of antipsychotics in blood at the time of death) (n = 12) and antipsychotic-treated (n = 12) subjects with schizophrenia, and matched controls (n = 24). Functional coupling of α₂-AR to G_α proteins induced by the agonist UK14304 was also tested. Additionally, G_α protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, α_2A-AR and α_2C-AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased α_2A-AR expression was found in synaptosomal plasma membrane and postsynaptic density (PSD) fractions (+60% and +79% vs controls, respectively) with no significant changes in α_2C-AR. [³⁵S]GTPγS SPA experiments showed a significant lower stimulation of G_αi2 and G_αi3 proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. G_αo protein stimulation was significantly decreased in both antipsychotic-free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of G_αi3 protein did not differ between groups, whereas G_αi2 levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. G_αo protein expression was increased in PSD of antipsychotic-treated subjects and in the presynaptic fraction of antipsychotic-free schizophrenia subjects. The present results suggest that antipsychotic treatment is able to modify in opposite directions both the protein expression and the functionality of α_2A-AR in the cortex of schizophrenia patients.