A Behavioral and Electroencephalographic Study of Anesthetic State Induced by MK-801 Combined with Haloperidol, Ketamine and Riluzole in Mice.

Abstract

Ketamine is an intravenous anesthetic that acts as a channel blocker on the N-methyl- d -aspartate (NMDA) receptor, a glutamate receptor subtype. MK-801 is the most potent compound among noncompetitive NMDA receptor antagonists. Ketamine induces loss of the righting reflex (LORR) in rodents, which is one of the indicators of unconsciousness, whereas high doses of MK-801 produce ataxia, but not LORR. In contrast, we previously reported that MK-801 combined with a low dose of the dopamine receptor antagonist haloperidol-induced LORR in mice. To assess a neurophysiologically distinct brain state and demonstrate unconsciousness, electroencephalograms (EEG) need to be examined together with LORR. Therefore, we herein investigated EEG changes after the systemic administration of MK-801 alone or in combination with haloperidol, and compared them with those induced by ketamine, the glutamate release inhibitor riluzole, and the γ-aminobutyric acid type A receptor agonist propofol. All drugs were intraperitoneally administered to adult male ddY mice (n = 168). General anesthesia was evaluated based on the righting reflex test. Animals who exhibited no righting for more than 30 seconds were considered to have LORR. In a separate group of mice, EEG of the primary visual cortex was recorded before and after the administration of MK-801 (3.0 mg/kg) alone or in combination with haloperidol (0.2 mg/kg), ketamine (150 mg/kg), riluzole (30 mg/kg), or propofol (240 mg/kg). The waveforms recorded were analyzed using EEG power spectra and spectrograms. The high dose of MK-801 alone did not induce LORR, whereas MK-801 combined with haloperidol produced LORR in a dose-dependent manner. Ketamine, riluzole, and propofol also dose-dependently induced LORR. In the EEG study, MK-801 alone induced a significant increase in δ power, while MK-801 plus haloperidol exerted similar effects on not only δ, but also θ and α power during LORR, suggesting that increases in δ, θ, and α power were necessary for LORR. The results obtained on MK-801 plus haloperidol were similar to those on ketamine in the behavioral and EEG studies, except for an increase in γ power by ketamine during LORR. Propofol significantly increased δ, θ, α, and β power during LORR. However, the EEG results obtained using riluzole, which produced a unique pattern of lower amplitude activity spanning most frequencies, markedly differed from those with the other drugs. This study revealed differences in EEG changes induced by various sedatives. The results obtained on MK-801 alone and MK-801 plus haloperidol suggest the importance of dopamine transmission in maintaining the righting reflex.