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

Previous evidence suggests that alpha(2)-adrenoceptors (alpha(2)-AR) may be involved in the pathophysiology of schizophrenia. However, postmortem brain studies on alpha(2)-AR expression and functionality in schizophrenia are scarce. The aim of our work was to evaluate alpha(2A)-AR and alpha(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 alpha(2)-AR to G(alpha) proteins induced by the agonist UK14304 was also tested. Additionally, G(alpha) protein expression was also evaluated. In antipsychotic-free schizophrenia subjects, alpha(2A)-AR and alpha(2C)-AR protein expression was similar to controls in all the subcellular fractions. Conversely, in antipsychotic-treated schizophrenia subjects, increased alpha(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 alpha(2C)-AR. [S-35]GTP(gamma)S SPA experiments showed a significant lower stimulation of G(alpha i2) and G(alpha i3) proteins by UK14304 in antipsychotic-treated schizophrenia subjects, whereas stimulation in antipsychotic-free schizophrenia subjects remained unchanged. G(alpha o) protein stimulation was significantly decreased in both antipsychotic free and antipsychotic-treated schizophrenia subjects compared to controls. Expression of G(alpha i3) protein did not differ between groups, whereas G(alpha i2) levels were increased in PSD of schizophrenia subjects, both antipsychotic-free and antipsychotic-treated. G(alpha o) 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 alpha(2A)-AR in the cortex of schizophrenia patients. (C) 2021 Elsevier B.V. and ECNP. All rights reserved.