Increased brain monoaminergic tone after the NMDA receptor GluN2A subunit gene knockout is responsible for resistance to the hypnotic effect of nitrous oxide

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• 作者：Andrey B. Petrenko^a ; ^{abpetr@med.niigata-u.ac.jp} ; Tomohiro Yamakura^a ; Tatsuro Kohno^a ; Kenji Sakimura^b ; Hiroshi Baba^a
• 关键词：N-methyl-d-aspartate receptor GluN2A subunit ; Knockout mouse ; Inhalational anesthetic ; Nitrous oxide ; Monoaminergic system ; Secondary effect
• 刊名：European Journal of Pharmacology
• 出版年：2013
• 出版时间：5 January, 2013
• 年：2013
• 卷：698
• 期：1-3
• 页码：200-205
• 全文大小：432 K

文摘

N-methyl-d-aspartate (NMDA) receptors can be inhibited by inhalational anesthetics in vitro at clinically relevant concentrations. Here, to clarify the role of NMDA receptors in anesthetic-induced unconsciousness, we examined the hypnotic properties of isoflurane, sevoflurane and nitrous oxide in NMDA receptor GluN2A subunit knockout mice. The hypnotic properties of inhalational anesthetics were evaluated in mice in the loss of righting reflex (LORR) assay by measuring the 50 % concentration for LORR (LORR ED₅₀). Knockout mice displayed isoflurane and sevoflurane LORR ED₅₀ values similar to wild-type controls, indicating no significant contribution of these receptors to the hypnotic action of halogenated anesthetics. However, compared with wild-type controls, mutant mice displayed larger isoflurane LORR ED₅₀ values in the presence of nitrous oxide, indicating a resistance to this gaseous anesthetic. Knockout mice have enhanced brain monoaminergic activity which occurs secondary to NMDA receptor dysfunction, and the observed resistance to the isoflurane LORR ED₅₀-sparing effect of nitrous oxide could be abolished by pretreatment with the dopamine D₂ receptor antagonist droperidol or with the serotonin 5-HT_2A receptor antagonist ketanserin. Thus, resistance to nitrous oxide in knockout mice appears to be a secondary phenomenon of monoaminergic origin and not a direct result of impaired NMDA receptor function. Our results indicate that NMDA receptors are not critically involved in the hypnotic action of conventionally-used inhalational anesthetics. Also, they suggest that increased brain monoaminergic tone can diminish the effects of general anesthesia. Finally, they provide further evidence that changes secondary to genetic manipulation can explain the results obtained in global knockouts.