Effects of the antipsychotics haloperidol, clozapine, and aripiprazole on the dendritic spine

Abstract Three types of antipsychotics, typical (e.g. haloperidol), atypical (e.g. clozapine), and dopamine partial agonist(e.g. aripiprazole), are administered for treatment of schizophrenia. These antipsychotics have different efficacy and side-effect profiles. We investigated whether aripiprazole, clozapine, and haloperidoldifferentially regulate the dendritic spinethrough the AKT- GSK-3beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidolwas administered to the rat cortical neurons. The levels of PSD95 protein and AKT- GSK-3beta cascade-related proteins were investigated by Western blot. The number of spines and PSD95 puncta were investigated by immunofluorescence cell staining. Aripiprazole(1 µM or 10 µM) and clozapine(1 µM) increased the levels of PSD95 protein, the number of spines, phosphorylated Akt Thr308 and Ser473, and phosphorylated GSK-3beta Ser9. On the other hand, haloperidol(1 µM or 10 µM) or an inappropriate concentration of clozapine(10 µM) decreased them. A GSK inhibitor also increased the levels of PSD-95 protein and caused the same morphology. Aripiprazole, clozapine, and haloperidoldifferentially regulate the dendritic spine, and this effect may occur through the AKT- GSK-3beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spinesin patients with schizophrenia.