Role of the gamma-aminobutyric acid receptor/chloride channel complex in tolerance to ethanol and cross-tolerance to diazepam and pentobarbital.
The role of the gamma-aminobutyric acid (GABA) receptor/chloride channel complex in the development of tolerance to ethanol and cross-tolerance to diazepam and pentobarbital was assessed. Rats given a low (1.8 g/kg) dose of ethanol before daily practice on the moving belt test of motor incoordination, and those given a high daily dose (3.6 g/kg) not paired with practice, showed tolerance to ethanol and cross-tolerance to diazepam and pentobarbital, whereas rats receiving 1.8 g/kg of ethanol after practice did not. Control rats were trained on the moving belt, but received no ethanol treatment. No differences were seen among the treatment groups in the abilities of GABA or ethanol to increase 36Cl uptake into cerebral cortical microsacs. However, diazepam potentiation of GABA-mediated chloride flux was significantly lower in rats receiving daily intoxicated practice, but only if they received an i.p. injection of ethanol 1 hr before sacrifice. The degree of pentobarbital potentiation of the effect of GABA did not correlate with the behavioral cross-tolerance observed. The results indicate that behaviorally augmented cross-tolerance from ethanol to diazepam correlates incompletely with changes on the biochemical level.
Mihic
S J
SJ
Department of Pharmacology, University of Toronto, Canada.
Kalant
H
H
Liu
J F
JF
Wu
P H
PH
D000818:Animals; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D004347:Drug Interactions; D004361:Drug Tolerance; D000431:Ethanol / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*
D018118:Chloride Channels; D002712:Chlorides; D007473:Ion Channels; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D000431:Ethanol; D010424:Pentobarbital; D003975:Diazepam