title: The effects of selective antagonists of serotonin 5-HT7 and 5-HT1A receptors on MK-801-induced impairment of learning and memory in the passive avoidance and Morris water maze tests in rats: mechanistic implications for the beneficial effects of the novel atypical antipsychotic lurasidone.
abstract: We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT(7) antagonist and 5-HT(1A) partial agonist activities, is superior to other antipsychotics in improving the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT(7) and 5-HT(1A) receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT(7) and 5-HT(1A) receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models.
authors.affiliation: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Horisawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.forename: Satoko
authors.initials: S
authors.lastname: Toma
authors.forename: Takeo
authors.initials: T
authors.lastname: Ishiyama
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Taiji
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects; D054833:Isoindoles / Q000627:therapeutic use*; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy; D000069056:Lurasidone Hydrochloride; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D013844:Thiazoles / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D054833:Isoindoles; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D013844:Thiazoles; C097216:serotonin 6 receptor; D044282:Receptor, Serotonin, 5-HT1A; D016291:Dizocilpine Maleate; D000069056:Lurasidone Hydrochloride