Chronic bretazenil produces tolerance to chlordiazepoxide, midazolam, and abecarnil

Abstract

The purpose of the present study was to determine if chronic treatment with a nonsedative benzodiazepine partial agonist would confer tolerance to the rate-decreasing effects of other benzodiazepine ligands in a fixed-interval procedure in rats. A separate group of rats was treated chronically with the sedative benzodiazepine full agonist, chlordiazepoxide, for comparison. It was hypothesized that tolerance would develop rapidly to chlordiazepoxide due to loss of reinforcement density at rate-decreasing doses and that there would probably be cross-tolerance to other rate-decreasing benzodiazepine ligands such as midazolam and abecarnil. Because bretazenil does not produce rate decreases, however, it was not expected that tolerance would be found to chlordiazepoxide, midazolam, or abecarnil. After 8–12 weeks of chronic treatment with either chlordiazepoxide or bretazenil, however (final dose of benzodiazepine = 30 mg/kg/day), tolerance was found to the rate-decreasing effects of chlordiazepoxide, midazolam, and abecarnil in both groups. It is concluded that such tolerance was most likely due to a saturation of benzodiazepine receptors by this high-affinity partial agonist.