Initial subsensitivity to anxiolytic treatments on conflict behavior in rats: parametric studies across drug classes

In conflict paradigms, benzodiazepines (BZs) often exhibit maximal anticonflict effects only after three to four BZ exposures (anxiolytic initial subsensitivity; AIS). The present experiments examined 1) whether AIS occurs with non-BZ anxiolytics and 2) whether prior exposure to non-BZs prevents the occurrence of BZ AIS. Female rats were trained to stable responding levels on a repeated-measures punished drinking paradigm. In Experiment 1, dose-response curves for the effects of the BZs chlordiazepoxide and diazepam, the barbiturates (BBs) pentobarbital and amobarbital, and the non-BZ, non-BB agent carbamazepine were determined in five groups of rats (one group/drug); dose-response curves were determined on two occasions for each drug. There was an AIS with both BZs, with the anticonflict effect being significantly greater for dose-response determination #2. There was no AIS with the BBs (robust and dose-dependent increases in punished responding on both determinations) or with carbamazepine (weak anticonflict effect on both determinations). In Experiment 2, the rats from Experiment 1 received a single-dose challenge with chlordiazepoxide (10 mg/kg). This challenge resulted in a robust anticonflict effect in subjects with a history of repeated BZ treatment; in contrast, subjects with a history of repeated BB or carbamazepine treatment exhibited smaller anticonflict responses. These data suggest that 1) the AIS does not occur with non-BZ anxiolytics and 2) the BZ AIS cannot be prevented by repeated exposure to non-BZs.