title: The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine-induced deficit in executive function in common marmosets.
abstract: Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia.
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Manato
authors.initials: M
authors.lastname: Kotani
authors.affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Murai
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nakako
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Iwamura
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kiyoshi
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ikejiri
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogi
authors.affiliation: Ikeda Lab, Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka, 564-0053, Japan. Electronic address: kazuhito-ikeda@ds-pharma.co.jp.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001578:Benzopyrans / Q000633:toxicity; D002144:Callithrix; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D056344:Executive Function / Q000187:drug effects*; D005260:Female; D007649:Ketamine / Q000633:toxicity; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D010078:Oxazines / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D014150:Antipsychotic Agents; D001578:Benzopyrans; D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D010078:Oxazines; D010879:Piperazines; D010880:Piperidines; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D007649:Ketamine; C079310:blonanserin
keywords: Blonanserin; Common marmoset; Dopamine D(3) receptor; Ketamine; Object retrieval with detour (ORD) task; Schizophrenia