Barbiturate tolerance: effects on GABA-operated chloride channel function.
Male ICR mice were fed powdered laboratory chow containing phenobarbital for 7 days to induce tolerance. Mice were sacrificed and brains assayed for changes in GABA-mediated chloride flux into brain membrane vesicles (microsacs). Concentration-dependent stimulation of chloride flux by GABA alone was not affected by the development of tolerance to phenobarbital. Phenobarbital potentiation of GABA-mediated chloride flux was significantly attenuated in the membranes prepared from phenobarbital-tolerant mice compared with those from pair-fed control mice. Similarly, stimulation of GABA-mediated flux by the benzodiazepine, flunitrazepam was also depressed in membranes from tolerant mice. However, the ability of ethanol and the benzodiazepine inverse agonist FG-7142 to modulate GABA-gated chloride flux was not affected by the development of phenobarbital tolerance. No significant changes in saturation [3H]diazepam binding parameters were observed. These findings suggest that there is a degree of cross-tolerance between phenobarbital and benzodiazepine agonist at the level of the GABA-operated chloride channel. Furthermore, although some reports have demonstrated behavioral cross-tolerance between ethanol and barbiturates, the present data suggest different mechanisms of tolerance development for these intoxicants at the level of the GABAA receptor chloride channel complex.
Allan
A M
AM
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO 63110.
Zhang
X
X
Baier
L D
LD
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001463:Barbiturates / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010634:Phenobarbital / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D014151:Anti-Anxiety Agents; D001463:Barbiturates; D002712:Chlorides; D007473:Ion Channels; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; D010634:Phenobarbital