Experimental dependence on barbiturates. II. Relationship between drug levels in serum and brain and the development of dependence in rats.

Feeding rats on food containing phenobarbital (PhB) (1 AND 2 mg/g) for 13 consecutive days resulted in the inhibition of motor coordination (by rotarod test) for 7 days, followed by a gradual decrease in the inhibition. PhB level in the serum reached a peak on the third day of feeding and then gradually decreased. PhB level in the brain, unlike that in the serum, gradually increased up to the seventh day and then decreased until the thirteenth day of feeding. Thus, alterations of the inhibited rotarod performance were depended on PhB level in the brain rather than on that in the serum. PhB level in the serum increased parallel to the graded increment in dosage from 0.5 and 1.0 mg/g to 4.0 mg/g, while that in the brain did not increase above the level on the seventh day of feeding on 1 and 2 mg/g food but remained relatively stable. PhB-dependent rats ate small amounts of drug-containing food incessantly day and night, and PhB levels in the serum and brain remained high and stable throughout the day. These phenomena suggest that the development of dependence on PhB is more intimately correlated with the length of application of the drug than with the magnitude of its dosage.