Circadian variation in tolerance to the hypothermic action of CNS drugs.

Male SAF mice (30-35 g) or male Sprague-Dawley rats (180-250 g) were used to study the circadian variation in tolerance to the hypothermic action of ethanol, apomorphine, and nicotine. Animals were treated for 2 or 3 consecutive days during the light phase (1000, 1400, or 1800 h) or the dark phase (2200, 0200, or 0600 h) and hypothermia produced measured. In one experiment, repeated injections of 20% ethanol (3 g/kg, IP) to mice resulted in varying degrees of hypothermia depending upon the time of injection. Tolerance to hypothermic action was observed only in animals treated during the light phase. On the contrary, the hypothermic response in animals treated during the dark phase increased. In another experiment, apomorphine (15 mg/kg, IP) was used and tolerance to apomorphine-induced hypothermia observed following repeated injections during the light phase with maximum tolerance noticed at 1400 h. In the third experiment, nicotine (2 mg/kg, IP) was repeatedly administered and resulted in tolerance development when given during the light phase. These results indicate that the rapid development of tolerance to CNS drugs studied is a diurnally controlled phenomenon.