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 (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reduced effect of diazepam and clonazepam to enhance GABA-stimulated 36Cl- influx in the tissue prepared from non-withdrawn rats.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.
Li
M
M
Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
Rosenberg
H C
HC
Chiu
T H
TH
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D002998:Clonazepam / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004361:Drug Tolerance; D005479:Flurazepam / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001570:Benzodiazepinones; D018118:Chloride Channels; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D005479:Flurazepam; C054626:bretazenil; D003975:Diazepam