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: Tomoko Horisawa, Hiroyuki Nishikawa, Satoko Toma, Atsushi Ikeda, Masakuni Horiguchi, Michiko Ono, Takeo Ishiyama, Mutsuo Taiji
• Journal: Behavioural brain research (Behav Brain Res) Vol. 244 Pg. 66-9 (May 01 2013) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 23376699 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• AS 19 compound
• Antipsychotic Agents
• Dopamine Antagonists
• Isoindoles
• Phenols
• Pyrazoles
• Pyrrolidines
• Receptors, Serotonin
• SB-656104-A
• Serotonin Antagonists
• Serotonin Receptor Agonists
• Tetrahydronaphthalenes
• Thiazoles
• serotonin 7 receptor
• Raclopride
• Dizocilpine Maleate
• Ketanserin
• Lurasidone Hydrochloride

Topics

• Animals
• Antipsychotic Agents (antagonists & inhibitors, pharmacology)
• Avoidance Learning (drug effects)
• Dizocilpine Maleate (antagonists & inhibitors, pharmacology)
• Dopamine Antagonists (pharmacology)
• Isoindoles (antagonists & inhibitors, pharmacology)
• Ketanserin (pharmacology)
• Lurasidone Hydrochloride
• Male
• Memory (drug effects)
• Phenols (pharmacology)
• Pyrazoles (pharmacology)
• Pyrrolidines (pharmacology)
• Raclopride (pharmacology)
• Rats
• Receptors, Serotonin (drug effects)
• Serotonin Antagonists (pharmacology)
• Serotonin Receptor Agonists (pharmacology)
• Tetrahydronaphthalenes (pharmacology)
• Thiazoles (antagonists & inhibitors, pharmacology)