TOLERANCE TO AND DEPENDENCE ON BARBITURATES IN MICE WITH REFERENCE TO THE DATA IN RATS

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AbstractThe experimental results on tolerance to and dependence on phénobarbital (PhB) in male, ICR mice were compared with results previously reported in the case of rats. When food admixed with 1 and 2 mg PhB/g food was administered daily for 13 consecutive days, the mice began to acquire tolerance to PhB from the 4th day or so (rotarod performance test), with little suppression being observed on days 6 or 7. These results indicate that tolerance to PhB is acquired earlier in mice than in rats. The blood and brain concentrations of PhB during the dosing period were reduced abruptly on the 3rd or 4th day, corresponding well with the time course changes in the development of tolerance shown by rotarod performance. The mice were given daily doses of PhB increasing stepwise from 0.5 and 1 mg PhB/g food to 4 mg PhB/g food, over 39 consecutive days. With this gradually increasing dose regimen, the animals maintained moderate to severe depression of CNS throughout the dosing period. The blood and brain half-life of PhB after withdrawal were 16 and 8 hr respectively. From 17 to 24 hours after withdrawal of PhB, the animals showed signs of systemic tremors, Straub-tail, hyperkinesia, wild running “rum fits” and clonic-tonic convulsions. Contrary to the findings in rats, in which there was a frequent incidence of convulsion from 17 to 48 hours after withdrawal, the duration of the characteristic signs after barbiturate withdrawal was obviously short-term. These results suggest that it may be more reasonable to use rats in preference to mice as a preclinical model of dependence, especially in cross-physical dependence tests for sedative-hypnotic drugs.