Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin–dopamine activity modulator: A role for serotonin 5-HT1A and 5-HT2A receptors

Abstract Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT) 1A , and dopamine D 2 receptors, and antagonistic activity at 5-HT 2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT 1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D 2 receptor antagonist, raclopride. Furthermore, the selective 5-HT 2A receptor antagonist M100907, but not DOI (5-HT 2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5-triphosphate (IP 3 ) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT 1A and 5-HT 2A receptors, and subsequent Ca 2+ signaling via IP 3 receptors.