α2A- and α2C-adrenoceptor expression and functionality in postmortem prefrontal cortex of schizophrenia subjects.

• α 2A - and α 2C -adrenoceptor protein expression was determined by Western Blot in the postmortem prefrontal cortex of 24 subjects with schizophrenia and 24 matched controls. • Experiments were performed in synaptosomal membranes (SPM) and in presynaptic (Pre) and postsynaptic density fractions (PSD). • Functional coupling of α 2 -AR to G α proteins induced by the agonist UK14304 was also tested. • In antipsychotic-treated schizophrenia subjects, increased α 2A -AR expression was found in SPM and PSD fractions. • G αi2 and G αi3 proteins mediated stimulation was lower in antipsychotic-treated schizophrenia subjects, whereas 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. Previous evidence suggests that α 2 -adrenoceptors (α 2 -AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on α 2 -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 α 2 -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. [ABSTRACT FROM AUTHOR]