Regional distribution of barbital in the brain of mice during the development of tolerance and physical dependence.

ICR male mice each receiving a 16 mg barbital pellet implanted subcutaneously for three days developed about 40 percent tolerance to barbital and more than 50 percent tolerance to pentobarbital as measured by sleeping time. The development of physical dependence in these mice was demonstrated by an increased sensitivity to convulsions with pentylenetetrazol. The concentration of barbital rose to high levels in the subcortex and the cerebellum during the time between the implantation of the pellet and the loss of the righting reflex and distributed uniformly thereafter. After a challenge dose of the drug, higher barbital concentrations were found in these two areas as well as in the pons-medulla at 30 minutes and in all areas at the time of the loss of righting reflex, in withdrawn mice. The latter finding would indicate an increase in threshold for barbital anesthesia. The mechanisms of the higher uptake in the brain of withdrawn mice are discussed.