Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide

The acute administration of ethanol, pentobarbital and chlordiazepoxide impaired, in a dose-dependent manner, the performance of rats on the moving-belt and two-way shuttle-box avoidance tests. Administration of these drugs for three weeks resulted in tolerance to their motor-impairing effects. Tolerance to ethanol or pentobarbital was characterized by a parallel shift of the dose-response curve to the right. Tolerance to chlordiazepoxide, however, was of greater extent and was accompanied by an apparent flattening of the dose-response curve. Symmetrical cross-tolerance developed between ethanol and pentobarbital. On the other hand, while chlordiazepoxide treatment conferred full cross-tolerance to ethanol and pentobarbital, only partial cross-tolerance to chlordiazepoxide was observed following treatment with ethanol or pentobarbital. These results suggest that at least part of the tolerance to chlordiazepoxide depends on changes in specific benzodiazepine receptors and is independent of the tolerance associated with non-specific changes in the cell membrane.