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

IF 4.6 2区 医学 Q1 ANESTHESIOLOGY Anesthesia and analgesia Pub Date : 2024-11-01 Epub Date: 2024-02-20 DOI:10.1213/ANE.0000000000006900
Yuka Kikuchi, Masahiro Irifune, Taiga Yoshinaka, Kana Oue, Tamayo Takahashi, Aya Oda, Hisanobu Kamio, Serika Imamura, Utaka Sasaki, Eiji Imado, Yukio Ago, Yoshiyuki Okada
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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MK-801 联合氟哌啶醇、氯胺酮和利鲁唑诱导小鼠麻醉状态的行为和脑电图研究
背景:氯胺酮是一种静脉麻醉剂,可作为谷氨酸受体亚型 N-甲基-d-天冬氨酸(NMDA)受体的通道阻断剂。MK-801 是非竞争性 NMDA 受体拮抗剂中最有效的化合物。氯胺酮会诱导啮齿类动物丧失向右转反射(LORR),这是昏迷的指标之一,而高剂量的 MK-801 会产生共济失调,但不会丧失向右转反射。相反,我们以前曾报道过 MK-801 与低剂量多巴胺受体拮抗剂氟哌啶醇联合使用可诱导小鼠出现 LORR。为了评估神经生理学上不同的大脑状态并证明昏迷,脑电图(EEG)需要与 LORR 一起检查。因此,我们在此研究了单独或与氟哌啶醇联合全身给药 MK-801 后的脑电图变化,并将其与氯胺酮、谷氨酸释放抑制剂利鲁唑和γ-氨基丁酸 A 型受体激动剂丙泊酚诱导的脑电图变化进行了比较:给成年雄性 ddY 小鼠(n = 168)腹腔注射所有药物。根据右旋反射测试评估全身麻醉情况。超过30秒不右转的小鼠被视为LORR。在另一组小鼠中,在单独或与氟哌啶醇(0.2 毫克/千克)、氯胺酮(150 毫克/千克)、利鲁唑(30 毫克/千克)或异丙酚(240 毫克/千克)联合使用 MK-801(3.0 毫克/千克)之前和之后,记录初级视觉皮层的脑电图。记录的波形使用脑电图功率谱和频谱图进行分析:结果:单独使用高剂量的 MK-801 不会诱导 LORR,而 MK-801 与氟哌啶醇联合使用则会以剂量依赖的方式产生 LORR。氯胺酮、利鲁唑和异丙酚也能以剂量依赖的方式诱导 LORR。在脑电图研究中,单用 MK-801 可显著增加δ功率,而 MK-801 加氟哌啶醇不仅对 LORR 期间的δ功率,还对θ和α功率产生类似的影响,这表明δ、θ和α功率的增加是 LORR 的必要条件。在行为和脑电图研究中,除了氯胺酮增加了 LORR 期间的 γ 功率外,使用 MK-801 加氟哌啶醇的结果与使用氯胺酮的结果相似。丙泊酚能明显增加 LORR 期间的 δ、θ、α 和 β 功率。然而,使用利鲁唑所获得的脑电图结果与使用其他药物所获得的结果明显不同,利鲁唑产生了一种跨越大多数频率的低振幅活动的独特模式:本研究揭示了各种镇静剂诱导的脑电图变化的差异。单用 MK-801 和 MK-801 加氟哌啶醇的结果表明,多巴胺传递在维持右旋反射中的重要性。
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来源期刊
Anesthesia and analgesia
Anesthesia and analgesia 医学-麻醉学
CiteScore
9.90
自引率
7.00%
发文量
817
审稿时长
2 months
期刊介绍: Anesthesia & Analgesia exists for the benefit of patients under the care of health care professionals engaged in the disciplines broadly related to anesthesiology, perioperative medicine, critical care medicine, and pain medicine. The Journal furthers the care of these patients by reporting the fundamental advances in the science of these clinical disciplines and by documenting the clinical, laboratory, and administrative advances that guide therapy. Anesthesia & Analgesia seeks a balance between definitive clinical and management investigations and outstanding basic scientific reports. The Journal welcomes original manuscripts containing rigorous design and analysis, even if unusual in their approach.
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