Activation of phosphoinositide 3-kinase delta by antipsychotic drugs: Preliminary results

Abstract Background/aims Catalytic subunit delta of phosphoinositide 3-kinase, p110δ, encoded by the PIK3CD gene, was recently proposed as a target for pharmacological treatment of schizophrenia. Current antipsychotic drugs were found to decrease the mRNA expression of PIK3CD , but the mechanism of this process is not known. The aim of the study was to elucidate the mechanism by which antipsychotic drugs affect the mRNA expression of PIK3CD . Methods The direct effect of haloperidol, clozapine, olanzapine, quetiapine and amisulpride on p110δ enzymatic activity was tested with a kinase assay, and the results were referenced against data on the mRNA expression of PIK3CD . Results Haloperidol, clozapine, olanzapine and quetiapine, but not amisulpride, at the concentration of 20–80 μM, were found to significantly increase enzymatic activity of p110δ by up to two times in a dose-dependent manner. Linear regression analysis revealed that more than 40% of the variance in antipsychotic drugs-induced changes in the expression of PIK3CD mRNA was explained only by changes in antipsychotic drug-regulated p110δ enzymatic activity ( p  = 0.011). Conclusions Antipsychotic drugs differentially increase the enzymatic activity of p110δ. This effect is associated with that of mRNA expression of the PIK3CD gene. Drug-enzyme interaction may explain the effect of antipsychotic drugs on the expression of PIK3CD mRNA, however, further studies are needed to investigate this hypothesis.