This study was designed to assess the strain differences in
pentobarbital toxicity,
narcosis, the development of tolerance and physical dependence, the half-life of
pentobarbital and the activities of hepatic microsomal electron transfer chain in DBA/2J, C57BL/6J and ICR mice. The comparisons of responses to acute
pentobarbital-induced
narcosis with two different doses revealed that DBA was most sensitive among these strains. When continuous administration of
pentobarbital by
pentobarbital pellet implantation is concerned, four criteria were used to assess strain differences: 1) determination of the duration of the loss of righting reflex during
pentobarbital pellet implantation; 2) cumulative mortality after
pentobarbital pellet implantation; 3) degree of tolerance development after 3 days of s.c. implantation of a 75-mg
pentobarbital pellet by the relative decrease in the
pentobarbital sleeping time; and 4) assessment of hyperexcitability by
pentylenetetrazol- and audiogenic-induced
seizures after pellet removal. The order of susceptibility to continuous
pentobarbital pellet implantation was found to be as follows: DBA/2J > C57BL/6J > ICR. The biochemical data also revealed that the half-life of
pentobarbital in DBA/2J mice was significantly longer than that of C57BL/6J or ICR mice in both brain and serum. Further studies also showed that DBA/2J mice have lower hepatic
cytochrome P-450 and
cytochrome b5 levels and
NADPH dehydrogenase and
NADPH-cytochrome c reductase activities as compared with the other strains of mice. However, these parameters were markedly induced in DBA/2J mice after the development of tolerance to
pentobarbital. It appears that the differences in genetic variation could be of importance for further studies in gaining insight of the mechanism of
barbiturate tolerance and dependence.