Alteration of convulsive threshold and sensitivity to CNS acting drugs in sedative-hypnotics-experienced rat...

The present study was made to investigate the developmental toxicity of ethanol and several sedative-hypnotics (barbital, diazepam, phenobarbital) administered to rat pups via dams for 18 days (day 3-21 after parturition) from the relatively early postnatal stage in terms of changes in the threshold for pentetrazol (PTZ)-induced convulsion, tolerance to, and physical dependence on barbital (B). In the pups of all dosed groups, the convulsive threshold for PTZ is reduced significantly compared with that in the naive group. The sleeping time with B in phenobarbital-exposed offspring was also reduced significantly compared with that in the naive pups. No difference was however, noted in the B concentration of the brain or plasma upon awaking between these groups of pups, which proved that the phenobarbital-exposed pups had obviously acquired a functional tolerance to B. B-dependence formation and the ensuring weight loss and appearance of withdrawal signs, especially clonic-tonic convulsion, were made intense in the phenobarbital-experienced pups. From these results, it may be concluded that exposure to sedative-hypnotics from the early CNS developing stage makes a lowered state of convulsive threshold for PTZ, and therefore, tends to enhance B-withdrawal convulsion. These phenomena were discussed from the viewpoint of monoamine metabolism in the brain.