BJA Advance Access originally published online on April 2, 2004
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British Journal of Anaesthesia, 2004, Vol. 92, No. 6 859-864
© 2004 The Board of Management and Trustees of the British Journal of Anaesthesia
Clinical Investigations |
Chronopharmacological studies of ketamine in normal and NMDA 
1 receptor knockout mice
1 Department of Anesthesiology, Jichi Medical School, Tochigi, Japan. 2 Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. 3 Department of Urology, Jichi Medical School, Tochigi, Japan. 4 Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
*Corresponding author. E-mail: eijikoba{at}jichi.ac.jp
Background. The effectiveness and toxicity of many drugs depends on the dosing-time schedule, relative to the circadian rhythms of biochemical, physiological, and behavioural processes. Previous studies have found chronopharmacology of ketamine, which is a N-methyl-D-aspartate (NMDA) receptor antagonist. The in vivo contribution of the NMDA receptor 
1 subunit (NR2A) in this effect is unclear.
Methods. In the present study, daily variations in the hypnotic effect of ketamine were determined in wild-type mice and NMDA 1 knockout (KO) mice.
Results. The effect of ketamine had a definite daily variation in wild-type mice. No significant difference in blood concentration was observed at different dosing times (10:00 and 22:00). In NMDA receptor 1 KO mice, the hypnotic effect of ketamine was weaker than in wild-type mice and there was no dependence on the time of administration. Significant pharmacokinetic differences were not observed between wild-type and KO mice.
Conclusions. The enhanced hypnotic effect in the active phase of the circadian cycle is likely a result of changes with the time of day in the susceptibility of the central nervous system to ketamine. Knockout of the NMDA receptor 1 subunit gene markedly reduced the effect of ketamine, and eliminated the time-dependent sensitivity to ketamine.
Br J Anaesth 2004; 92: 859–64
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