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ANESTHETIC PHARMACOLOGY

Reduced Sensitivity to Ketamine and Pentobarbital in Mice Lacking the N-Methyl-D-Aspartate Receptor GluR1 Subunit

Andrey B. Petrenko, MD^*,, Tomohiro Yamakura, MD PhD^*, Naoshi Fujiwara, PhD, Ahmed R. Askalany, MD^*, Hiroshi Baba, MD PhD^*, and Kenji Sakimura, PhD

*Department of Anesthesiology, Niigata University School of Medicine, Niigata, Japan; Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata; and Department of Medical Technology, Niigata University School of Health Sciences, Niigata, Japan

Address correspondence and reprint requests to Tomohiro Yamakura, MD, PhD, Department of Anesthesiology, Niigata University School of Medicine, Asahimachi 1-757, Niigata 951-8510, Japan. Address e-mail to yamakura{at}med.niigata-u.ac.jp

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 GluR1 (NR1) subunit with GluR (GluR1–4; NR2A–D) subunits, which confer unique properties on native NMDARs. We hypothesized that animals deficient in GluR1, 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 GluR1 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 GluR1 subunit in mediation of ketamine anesthesia/hypnosis, they suggest the difficulties with interpretation of altered anesthetic sensitivity in knockout animal models.

IMPLICATIONS: Mice deficient in the N-methyl-D-aspartate (NMDA) receptor GluR1 subunit showed reduced sensitivity to the anesthetic/hypnotic actions of ketamine. Sensitivity to pentobarbital, which, unlike ketamine, does not interact with NMDA receptors at clinically relevant concentrations, was also reduced. Our results illustrate the difficulties with interpreting altered anesthetic sensitivity in knockout animal models.

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