Genetic selection for benzodiazepine ataxia produces functional changes in the gamma-aminobutyric acid receptor chloride channel complex.

Article date: 1988/6/14

PubMed ID: 2456824

Journal name: Brain research (ISSN: 0006-8993)


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)

This document is available from: http://directlinks.cc/files/muscimol/2456824.pdf

Author List: Allan A M, Gallaher E J, Gionet S E, Harris R A

Publication Types: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Chlorides; Ion Channels; Isoxazoles; Receptors, GABA-A; Muscimol; Ethanol; Flunitrazepam; gaboxadol; Diazepam; Phenobarbital;

Mesh terms: Animals; Ataxia/chemically induced; Chlorides/pharmacokinetics; Diazepam/pharmacology; Ethanol/pharmacology; Flunitrazepam/pharmacology; Ion Channels/physiology; Isoxazoles/pharmacology; Mice; Muscimol/pharmacology; Phenobarbital/pharmacology; Receptors, GABA-A/genetics; Time Factors;

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