title: Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D₃-5-HT₂A and D₁-NMDA receptors in the mPFC.
abstract: Blonanserin differs from currently used serotonin 5-HT₂A/dopamine-D₂ receptor antagonists in that it exhibits higher affinity for dopamine-D₂/₃ receptors than for serotonin 5-HT₂A receptors. We investigated the involvement of dopamine-D₃ receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT₂A receptor agonist) and 7-OH-DPAT (a dopamine-D₃ receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D₁ receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D₁-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D₃ and serotonin 5-HT₂A receptors in the mPFC.
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Hida
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Mori
authors.affiliation: 1] Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan [2] Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Regional Pharmaceutical Care and Science, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Seki
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Iwamoto
authors.affiliation: Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Regional Pharmaceutical Care and Science, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D000077152:Olanzapine; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D000662:Amphetamines; D001552:Benzazepines; D018491:Dopamine Agonists; D007546:Isoquinolines; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D016194:Receptors, N-Methyl-D-Aspartate; C534628:SCH 23390; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D001569:Benzodiazepines; C079310:blonanserin; D010622:Phencyclidine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000077152:Olanzapine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine