title: Clozapine ameliorates epigenetic and behavioral abnormalities induced by phencyclidine through activation of dopamine D1 receptor.
abstract: Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca²⁺/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Toriumi
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Takenao
authors.initials: T
authors.lastname: Koseki
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Narusawa
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ikawa
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.affiliation: The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes, Meijo University, Nagoya, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.affiliation: The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes, Meijo University, Nagoya, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D020148:Butyric Acid / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005106:Exploratory Behavior / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced; D051379:Mice; D008813:Mice, Inbred ICR; D010622:Phencyclidine / Q000494:pharmacology; D010623:Phencyclidine Abuse / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D006213:Hallucinogens; D006633:Histamine Antagonists; D006657:Histones; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D020148:Butyric Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol