Bidirectional contingent cross tolerance between the anticonvulsant effects of pentobarbital and ethanol

In Experiment 1, two groups of kindled rats received a pentobarbital injection (15 mg/kg, IP) and a convulsive amygdala stimulation once every 48 h. In one group, pentobarbital was injected 1 h before each stimulation; in the other, it was injected 1 h after each stimulation. Only the rats that received pentobarbital before each stimulation became tolerant to pentobarbital's anticonvulsant effect. Cross tolerance to the anticonvulsant effect of ethanol (1.5 g/kg, IP) was also found to be greater in the pentobarbital-before-stimulation rats. Experiment 2 was designed to assess the transfer of tolerance in the opposite direction, that is, from ethanol to pentobarbital, and the results mirrored those of Experiment 1: convulsive stimulation during the periods of ethanol exposure facilitated the development of tolerance to the anticonvulsant effect of ethanol and its transfer to pentobarbital. These results support the theory that functional drug tolerance and cross tolerance are adaptations to the effects of drugs on concurrent patterns of neural activity rather than to drug exposure per se.