Chronopharmacological studies of ketamine in normal and NMDA epsilon1 receptor knockout mice.
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 epsilon1 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 epsilon1 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 epsilon1 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 epsilon1 subunit gene markedly reduced the effect of ketamine, and eliminated the time-dependent sensitivity to ketamine.
Sato
Y
Y
Department of Anesthesiology, Jichi Medical School, Tochigi, Japan.
Kobayashi
E
E
Hakamata
Y
Y
Kobahashi
M
M
Wainai
T
T
Murayama
T
T
Mishina
M
M
Seo
N
N
D000778:Anesthetics, Dissociative / Q000008:administration & dosage* / Q000097:blood; D000818:Animals; D019454:Chronotherapy; D002940:Circadian Rhythm; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004326:Drinking / Q000502:physiology; D007649:Ketamine / Q000008:administration & dosage* / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*
D000778:Anesthetics, Dissociative; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D003577:Cytochrome P-450 Enzyme System