title: 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 D2 receptors, and antagonistic activity at 5-HT2A 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-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A 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 (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca(2+) signaling via IP3 receptors.
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors: Tamaki
authors: T
authors: Ishima
authors: Qs׳ Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Takashi
authors: T
authors: Futamura
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Qs׳ Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Yuta
authors: Y
authors: Ohgi
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan; Qs׳ Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Noriko
authors: N
authors: Yoshimi
authors: Qs׳ Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Tetsuro
authors: T
authors: Kikuchi
authors: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address: hashimoto@faculty.chiba-u.jp.
authors: Kenji
authors: K
authors: Hashimoto
mesh_terms: D000818:Animals; D000068180:Aripiprazole / Q000627:therapeutic use; D001896:Boron Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005464:Fluorobenzenes / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000494:pharmacology; D020932:Nerve Growth Factor; D016501:Neurites / Q000187:drug effects*; D010080:Oxazoles / Q000494:pharmacology; D016716:PC12 Cells; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D001896:Boron Compounds; D005464:Fluorobenzenes; D018841:HSP90 Heat-Shock Proteins; C588351:Hsp90aa1 protein, rat; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D013876:Thiophenes; C511704:xestospongin C; D044282:Receptor, Serotonin, 5-HT1A; C000591922:brexpiprazole; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000068180:Aripiprazole; D020932:Nerve Growth Factor; C109986:2-aminoethoxydiphenyl borate; C079049:volinanserin
keywords: 5-HT(1A) receptor; 5-HT(2A) receptor; Brexpiprazole; Ca(2+)signaling; IP(3) receptors; Neurite outgrowth