Circadian rhythm in hexobarbital sleep time: a dose-response evaluation in the mouse

Studies were conducted in an effort to determine if a circadian rhythm in response of mice to hexobarbital could be evaluated employing dose-response curves. Results showed a circadian change in both the position and slope of the dose-response curves when evaluated at 0800, 1400, 2000 and 0200 hours. Sleep times were longer at 0800 hours and shortest at 0200 hours, in the dark period. Greatest differences between slopes of the curves were noted when 1400 and 0200 as well as 0800 and 2000 hours were compared. Slopes were significantly flatter during the dark cycle relative to the light cycle suggesting altered rates of disposition of the drug. Measurements of in vitro hepatic metabolism of hexobarbital, p-nitro-anisole and aminopyrine at 0200 and 1400 hours demonstrated a significant rhythm in oxidative drug metabolism with maximal activity at 0200 hours. The results show that a rhythm in the duration of action of hexobarbital in mice is dose-dependent and that this rhythm is inversely related to a similar rhythm in microsomal drug metabolism. The rhythm in response to this agent may be subserved by a rhythm in drug metabolism.