Effect of N-methyl-D-aspartate receptor epsilon1 subunit gene disruption of the action of general anesthetic drugs in mice.

BACKGROUND Recent molecular strategies demonstrated that the N-methyl-d-aspartate (NMDA) receptor is a major target site of anesthetic agents. In a previous article, the authors showed that knocking out the NMDA receptor epsilon1 subunit gene markedly reduced the hypnotic effect of ketamine in mice. In the current study, the authors examined the in vivo contribution of the NMDA receptor epsilon1 subunit to the action of other anesthetic drugs. METHODS The authors determined the anesthetic effects of nitrous oxide on sevoflurane potency in NMDA receptor epsilon1 subunit knockout mice compared with those in wild-type mice. They then tested the hypnotic effect of gamma-aminobutyric acid-mediated agents, such as propofol, pentobarbital, diazepam, and midazolam, in knockout mice and wild-type mice. RESULTS The anesthetic action of sevoflurane itself was unaffected by the abrogation of the NMDA receptor epsilon1 subunit. Adding nitrous oxide reduced the required concentration of sevoflurane to induce anesthesia in wild-type mice, whereas this sparing effect was diminished in knockout mice. Furthermore, propofol, pentobarbital, diazepam, and midazolam also had markedly attenuated effects in knockout mice. CONCLUSIONS Although it has been demonstrated that knocking out the expression of receptors may induce changes in the composition of the subunits, the network circuitry, or both, the current findings show consistently that the NMDA receptor epsilon1 subunit mediates nitrous oxide but not sevoflurane anesthesia. Furthermore, the attenuated anesthetic impact of propofol, pentobarbital, diazepam, and midazolam as well as ketamine in knockout mice suggests that the NMDA receptor epsilon1 subunit could be indirectly involved in the hypnotic action of these drugs in vivo.