Genetic selection for benzodiazepine ataxia produces functional changes in the gamma-aminobutyric acid receptor chloride channel complex.
The gamma-aminobutyric acid (GABA) receptor-operated chloride channel complex was evaluated in mice selected for differential sensitivity to the ataxic effects of diazepam (diazepam-sensitive (DS) and diazepam-resistant (DR) lines). The ataxic effects of several drugs purported to produce some of their actions through the benzodiazepine-GABA receptor complex were examined using the rotarod test. The duration of impairment produced by diazepam, ethanol, 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol (THIP) and phenobarbital was greater in the diazepam-sensitive than in the diazepam-resistant mice. In contrast, pentobarbital produced an equivalent duration of ataxia in the two lines. Muscimol-stimulated 36Cl- influx and the binding of [35S]t-butylbicyclophosphorothionate (TBPS) and [3H]flunitrazepam were measured using isolated brain membrane vesicles (microsacs). Depolarization-dependent 45Ca2+ uptake was measured in whole brain synaptosomes. Muscimol was a more potent stimulator of 36Cl- flux in the DS compared to the DR mice, although no difference between the lines was found in muscimol-stimulation of [3H]flunitrazepam binding. Flunitrazepam augmented the muscimol-stimulated 36Cl- uptake in the DS but not in the DR mice. However, no differences between the lines of mice were found in either density or affinity of [3H]flunitrazepam binding sites. Similarly, no differences in either the density or affinity of [35S]TBPS binding sites was found. Ethanol (10-45 mM) potentiated the muscimol-stimulation of 36Cl- in DS, with no effect in DR mice. However, ethanol inhibition of [35S]TBPS binding was equivalent in the two lines of mice. Pentobarbital produced an equal potentiation of the muscimol-stimulated 36Cl- flux in the two lines, but phenobarbital potentiated the muscimol-induced 36Cl- influx slightly more in DS mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Allan
A M
AM
Research Service, VA Medical Center, Denver, CO 80262.
Gallaher
E J
EJ
Gionet
S E
SE
Harris
R A
RA
D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000493:pharmacokinetics / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D007473:Ion Channels / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D009118:Muscimol / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics* / Q000502:physiology; D013997:Time Factors
D002712:Chlorides; D007473:Ion Channels; D007555:Isoxazoles; D011963:Receptors, GABA-A; D009118:Muscimol; D000431:Ethanol; D005445:Flunitrazepam; C015542:gaboxadol; D003975:Diazepam; D010634:Phenobarbital