title: Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms.
abstract: Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30-80 Hz) power. MK-801 (0.05-0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose-response curve; at higher doses (0.3-1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130-180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5-4 Hz) power at higher doses. PCP (1.25-10 mg/kg) and ketamine (2.5-30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10-30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1-10 mg/kg) and DOI (0.5-2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition.
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: Tetsuaki
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: Daiji
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: Jun-ichi
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: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D065818:Gamma Rhythm / Q000187:drug effects* / Q000502:physiology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D008694:Methamphetamine / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000662:Amphetamines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D008694:Methamphetamine; D007649:Ketamine; D016291:Dizocilpine Maleate; D010622:Phencyclidine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D008559:Memantine
keywords: Delta band oscillation; Gamma band oscillation; High-frequency oscillation; Hyperglutamatergic state; NMDA receptor antagonist; Schizophrenia