title: Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms.
abstract: Hypofunction of the N-methyl-D-aspartic acid receptor (NMDAr) has been considered to play a crucial role in the pathophysiology of schizophrenia. In rodent electroencephalogram (EEG) studies, non-competitive NMDAr antagonists have been reported to produce aberrant basal gamma band oscillation (GBO), as observed in schizophrenia. Aberrations in GBO power have attracted attention as a translational biomarker for the development of novel antipsychotic drugs. However, the neuronal mechanisms as well as the pharmacological significance of NMDAr antagonist-induced aberrant GBO power have not been fully investigated. In the present study, to address the above questions, we examined the pharmacological properties of MK-801 (0.1 mg/kg)-increased basal GBO power in rat cortical EEG. Riluzole (3-10 mg/kg), a glutamate release inhibitor, reduced the MK-801-increased basal GBO power. In contrast, L-838,417 (1-3 mg/kg), an α2/3/5 subunit-selective GABAA receptor-positive allosteric modulator, enhanced the GBO increase. Antipsychotics such as haloperidol (0.05-0.3 mg/kg) and clozapine (1-10 mg/kg) dose-dependently attenuated the MK-801-increased GBO power. Likewise, LY379268 (0.3-3 mg/kg), an metabotropic glutamate 2/3 receptor (mGlu2/3 receptor) agonist, reduced the GBO increase in a dose-dependent manner, which was antagonized by an mGlu2/3 receptor antagonist LY341495. These results suggest that an increase in cortical GBO power induced by NMDAr hypofunction can be attributed to the aberrant activities of both excitatory pyramidal neurons and inhibitory interneurons in local circuits. The aberrant cortical GBO power reflecting cortical network dysfunction observed in schizophrenia might be a useful biomarker for the discovery of novel antipsychotic drugs.
authors.affiliation: Pharmacology 1, Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. Electronic address: t-hiyoshi@so.taisho.co.jp.
authors.forename: T
authors.initials: T
authors.lastname: Hiyoshi
authors.affiliation: Pharmacology 1, Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Kambe
authors.affiliation: Pharmacology 1, Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Karasawa
authors.affiliation: Pharmacology 1, Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D065818:Gamma Rhythm / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; D005464:Fluorobenzenes; D018682:GABA Agents; C118218:LY 379268; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D019782:Riluzole; C409903:L 838,417; D003024:Clozapine; D006220:Haloperidol
keywords: NMDA receptor antagonist; antipsychotic drug; gamma band oscillation; mGlu2/3 receptor; schizophrenia