Critical involvement of the orbitofrontal cortex in hyperlocomotion induced by NMDA receptor blockade in mice

Kaoru Seiriki; Atsushi Kasai; Takahiro Kuwaki; Takanobu Nakazawa; Shun Yamaguchi; Hitoshi Hashimoto

doi:10.1016/j.bbrc.2016.10.089

Critical involvement of the orbitofrontal cortex in hyperlocomotion induced by NMDA receptor blockade in mice

Biochem Biophys Res Commun. 2016 Nov 25;480(4):558-563. doi: 10.1016/j.bbrc.2016.10.089. Epub 2016 Oct 25.

Authors

Kaoru Seiriki¹, Atsushi Kasai¹, Takahiro Kuwaki¹, Takanobu Nakazawa², Shun Yamaguchi³, Hitoshi Hashimoto⁴

Affiliations

¹ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan.
³ Division of Morphological Neuroscience, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
⁴ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: hasimoto@phs.osaka-u.ac.jp.

PMID: 27793672
DOI: 10.1016/j.bbrc.2016.10.089

Abstract

Glutamatergic N-methyl-d-aspartate (NMDA) receptors play critical roles in several neurological and psychiatric diseases. Blockade by noncompetitive NMDA receptor antagonist leads to psychotomimetic effects; however, the brain regions responsible for the effects are not well understood. Here, we determined the specific brain regions responsive to MK-801, a noncompetitive NMDA receptor antagonist, by mapping Arc expression as an indicator of neuronal activity using Arc::dVenus reporter mice. MK-801 increased dVenus expression predominantly in the orbitofrontal cortex (OFC) and, as expected, induced a marked hyperlocomotion. Local OFC lesions selectively attenuated the early phase (0-30 min) of MK-801-induced hyperlocomotion. Further, clozapine, an atypical antipsychotic, effectively attenuated both the MK-801-induced dVenus expression in the OFC and hyperlocomotion. These results suggest that the OFC may be critically involved in NMDA receptor-mediated psychotic-like behavioral abnormalities.

Keywords: Antipsychotic; Arc; Clozapine; Hyperlocomotion; NMDA receptor antagonist; Orbitofrontal cortex.

MeSH terms

Animals
Dizocilpine Maleate / pharmacology*
Frontal Lobe / drug effects
Frontal Lobe / physiopathology*
Hyperkinesis / chemically induced
Hyperkinesis / physiopathology*
Locomotion / drug effects*
Male
Mice
Mice, Inbred C57BL
Nerve Net / drug effects
Nerve Net / physiopathology
Prefrontal Cortex / drug effects
Prefrontal Cortex / physiopathology*
Psychoses, Substance-Induced / physiopathology*
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
Receptors, N-Methyl-D-Aspartate / metabolism

Substances

Receptors, N-Methyl-D-Aspartate
Dizocilpine Maleate