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

• Published in: European neuropsychopharmacology 2018-05, Vol.28 (5), p.610-619
• Main Authors: Takaki, Manabu, Kodama, Masafumi, Mizuki, Yutaka, Kawai, Hiroki, Yoshimura, Bunta, Kishimoto, Makiko, Sakamoto, Shinji, Okahisa, Yuko, Yamada, Norihito
• Format: Article
• Language: English
• Subjects: Animals; Aripiprazole; Aripiprazole - pharmacology; Cerebral Cortex - metabolism; Clozapine; Clozapine - pharmacology; Dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - enzymology; Disks Large Homolog 4 Protein - biosynthesis; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Haloperidol; Haloperidol - pharmacology; Indoles - pharmacology; Maleimides - pharmacology; Phosphorylation - drug effects; Primary Cell Culture; Proto-Oncogene Proteins c-akt - metabolism; PSD95; Rats; Signal Transduction - drug effects
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2018.03.004

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 haloperidol differentially regulate the dendritic spine through the AKT-GSK-3 beta cascade. Dissociated cortical neurons from Sprague-Dawley rats were prepared and cultured for 28 days. Aripiprazole, clozapine, or haloperidol was administered to the rat cortical neurons. The levels of PSD95 protein and AKT-GSK-3 beta 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-3 beta 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 haloperidol differentially regulate the dendritic spine, and this effect may occur through the AKT-GSK-3 beta cascade. Selection and appropriate dose of these antipsychotics may be important for the protection of dendritic spines in patients with schizophrenia.