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  • Title: Tolerance to the effects of diazepam, clonazepam and bretazenil on GABA-stimulated Cl- influx in flurazepam tolerant rats.
    Author: Li M, Rosenberg HC, Chiu TH.
    Journal: Eur J Pharmacol; 1993 Nov 15; 247(3):313-8. PubMed ID: 8307102.
    Abstract:
    The effect of chronic flurazepam treatment on the GABA (gamma-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 effect, which did not reach statistical significance in the tissue from control rats. There was no significant change in the basal or 10 microM 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reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl- influx in the tissue prepared from non-withdrawn rats.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.
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