Ketamine is an IV anesthetic with N-methyl-d-aspartate receptor (NMDAR)-blocking properties. However, it is still unclear whether ketamine's general anesthetic actions are mediated primarily via blockade of NMDAR. Functional NMDARs are composed by the assembly of a GluRzeta1 (NR1) subunit with GluRepsilon (GluRepsilon1-4; NR2A-D) subunits, which confer unique properties on native NMDARs. We hypothesized that animals deficient in GluRepsilon1, an abundant and ubiquitously postnatally expressed NMDAR subunit, might be resistant to the effects of ketamine. Here, we evaluated a righting reflex to determine the general anesthetic/hypnotic potency of ketamine administered intraperitoneally to GluRepsilon1 knockout mice and compared these results with those for wild-type mice. Mutant mice were more resistant to ketamine than control mice. Unexpectedly, mutant mice were also more resistant to pentobarbital, which is thought not to interact with NMDAR at clinically relevant concentrations. Although these data in no way eliminate the possibility of the involvement of the NMDAR GluRepsilon1 subunit in mediation of ketamine anesthesia/hypnosis, they suggest the difficulties with interpretation of altered anesthetic sensitivity in knockout animal models.