Tolerance to the effects of diazepam, clonazepam and bretazenil on GABA-stimulated Cl − influx in flurazepam tolerant rats

The effect of chronic flurazepam treatment on the GABA (γ-aminobutyric acid) receptor / chloride channel complex was studied using GABA-stimulated 36Cl − influx into brain microsacs, and its potentiation by diazepam, clonazepam and bretazenil. Rats were given flurazepam for 1 week, then microsacs were prepared from cerebral cortices of rats that were still receiving flurazepam, and from those that had stopped treatment 48 h earlier. Diazepam and clonazepam produced concentration-dependent increases in GABA-stimulated 36Cl − influx while bretazenil produced a much smaller, which did not reach statistical significance in the tissue from control rats. There was no significant change in the basal or 10 μM GABA-stimulated 36Cl − influx between control and treated groups. Tolerance was shown by a significantly reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl − influx in the tissue prepared from non-withdrawn rats. However, for both diazepam and clonazepam, there was no tolerance 48 h after chronic treatment. The results suggest that changes in the GABA receptor/Cl − channel complex on cerebral cortical neurons contribute to cross-tolerance from flurazepam to other benzodiazepines.