title: The role of 5-HT7 receptor antagonism in the amelioration of MK-801-induced learning and memory deficits by the novel atypical antipsychotic drug lurasidone.
abstract: Lurasidone is a novel atypical antipsychotic with high affinity for dopamine D2, serotonin 5-HT7 and 5-HT2A receptors. We previously reported that lurasidone and the selective 5-HT7 receptor antagonist, SB-656104-A improved learning and memory deficits induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, in the rat passive avoidance test. In this study, we first examined the role of the 5-HT7 receptor antagonistic activity of lurasidone in its pro-cognitive effect to ameliorate MK-801-induced deficits in the rat passive avoidance test. The 5-HT7 receptor agonist, AS19, (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin, (3 mg/kg, s.c.) completely blocked the attenuating effects of lurasidone (3 mg/kg, p.o.), highlighting the importance of 5-HT7 receptor antagonism in the pro-cognitive effect of lurasidone. AS19 (3 mg/kg, s.c.) also blocked the ameliorating effect of SB-656104-A (10 mg/kg, i.p.) in the same experimental paradigm. To further extend our observation, we next tested whether 5-HT7 receptor antagonism still led to the amelioration of MK-801-induced deficits when combined with D2 and 5-HT2A receptor antagonists, and found that SB-656104-A (10 mg/kg, i.p.) significantly ameliorated MK-801-induced deficits even in the presence of the D2 receptor antagonist raclopride (0.1 mg/kg, s.c.) and 5-HT2A receptor antagonist ketanserin (1 mg/kg, s.c.). Taken together, these results suggest that the 5-HT7 receptor antagonistic activity of lurasidone plays an important role in its effectiveness against MK-801-induced deficits, and may contribute to its pharmacological actions in patients with schizophrenia.
authors: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. tomoko-horisawa@ds-pharma.co.jp
authors: Tomoko
authors: T
authors: Horisawa
authors: Hiroyuki
authors: H
authors: Nishikawa
authors: Satoko
authors: S
authors: Toma
authors: Atsushi
authors: A
authors: Ikeda
authors: Masakuni
authors: M
authors: Horiguchi
authors: Michiko
authors: M
authors: Ono
authors: Takeo
authors: T
authors: Ishiyama
authors: Mutsuo
authors: M
authors: Taiji
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D054833:Isoindoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology; D000069056:Lurasidone Hydrochloride; D008297:Male; D008568:Memory / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C505862:AS 19 compound; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D054833:Isoindoles; D010636:Phenols; D011720:Pyrazoles; D011759:Pyrrolidines; D011985:Receptors, Serotonin; C475591:SB-656104-A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; C104425:serotonin 7 receptor; D020891:Raclopride; D016291:Dizocilpine Maleate; D007650:Ketanserin; D000069056:Lurasidone Hydrochloride