Tolerance/cross-tolerance to the discriminative stimulus effects of chlordiazepoxide and bretazenil.

Rats were trained to discriminate 10 mg/kg chlordiazepoxide (CDAP) from saline in a two-lever drug discrimination procedure. Both CDAP and the nonsedative benzodiazepine partial agonist, bretazenil, dose-dependently substituted for the training dose of CDAP. Training was then suspended and half of the rats were placed on chronic CDAP, while the other half received water. Tolerance to the discriminative stimulus effects of CDAP developed after 1 mo and a final dose of approximately 110 mg/kg/d, as evidenced by the fact that the training dose of CDAP no longer produced drug-appropriate responding. An insurmountable tolerance also developed to bretazenil, as no rat responded on the drug-appropriate lever at doses as high as 56 mg/kg, whereas in the prechronic dose-effect curve, 1 mg/kg of bretazenil produced 100% drug-appropriate responding. One week after chronic CDAP was discontinued, the dose-effect curve for CDAP in the chronic CDAP group was comparable to that obtained in the prechronic phase, indicating that the rats were no longer tolerant to CDAP. In contrast to CDAP, the dose-effect curve for bretazenil did not return to its prechronic level, with higher doses being required for substitution. In the chronic water group, the dose-effect curves for CDAP and bretazenil were essentially the same before, during, and after the chronic regimen. Thus, suspension of training for 6 wk does not result in loss of the discriminative stimulus control. Chronic exposure to CDAP, however, does result in tolerance to the discriminative stimulus effects of CDAP, with an accompanying insurmountable cross-tolerance to the partial benzodiazepine agonist, bretazenil. These results support findings by other investigators who find tolerance to the discriminative stimulus properties of a wide range of psychoactive drugs (Young and Sannerud, 1989).