Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum

Abstract

Background: It has been demonstrated that schizophrenics have altered levels and/or phosphorylation states of several Wnt related proteins in the brain, including beta-catenin and GSK-3, and may represent susceptibility loci for schizophrenia. The current study was conducted to assess the effects of antipsychotics on beta-catenin and glycogen synthase kinase-3.

Methods: Western blotting and immunocytochemistry were employed to investigate the effects of antipsychotics on beta-catenin and glycogen synthase kinase-3 following acute, subchronic and chronic drug administration. Specificity of the response was tested using additional drugs such as fluoxetine, amphetamine and valproic acid.

Results: Significant increases in the levels of beta-catenin and glycogen synthase kinase-3 total protein were identified following administration of clozapine, haloperidol or risperidone. The phosphorylation state of GSK-3 was also increased but phosphorylated beta-catenin levels were unaffected. Other drug compounds, with the exception of raclopride, had no effect on either GSK-3 or beta-catenin protein levels or distribution.

Conclusions: Targeting of beta-catenin and GSK-3 is a common feature of antipsychotics regardless of class and appears to be mediated by D(2) dopamine receptors. Therefore changes in beta-catenin and GSK-3 may represent one of the mechanisms through which antipsychotics are able to exert behavioral changes.