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

Potentiation of γ‐Aminobutyric Acid‐Mediated Chloride Flux by Pentobarbital and Diazepam but Not Ethanol

“…In cerebellar microsacs prepared from ethanol-sensitive long-sleep (LS) mice, ethanol (15-50 mM) potentiated muscimol stimulation of 36C1uptake, but it had no effect at all in cerebellar microsacs from ethanol-resistant short-sleep (SS) mice or in hippocampal microsacs from either LS or SS mice (Allan and Harris, 1986). Similarly, ethanol (10-45 mM) enhanced this uptake in preparations from diazepam-sensitive (DS) but not from diazepam-resistant (DR) mice (Allan et al, 1988a) and in those from rats bred for high acute sensitivity to ethanol but not from low acute sensitivity rats (Allan et al, 1988b). In contrast, pentobarbital enhancement of muscimol-stimulated C1flux was seen equally in LS and DS mice (Allan and Hams, 1986) and in DS and DR mice (Allan et al, 1988~).…”

GabaA Receptors: Pharmacology, Behavioral Roles, and Motor Disorders

“…Differences between animals were evaluated in their rotarod performance, which is a measure of motor function, but care was taken that the animals were not impaired under control conditions. Ligand-binding assays did not detect any drastic alterations of GABAA receptors in the diazepam-sensitive lines (79). However, GABAA receptors of diazepamsensitive mice exhibit a high functional sensitivity to BZ agonists and to ethanol similar to that of mouse lines selected for high sensitivity to ethanol-induced hypnosis (79,80).…”

“…Ligand-binding assays did not detect any drastic alterations of GABAA receptors in the diazepam-sensitive lines (79). However, GABAA receptors of diazepamsensitive mice exhibit a high functional sensitivity to BZ agonists and to ethanol similar to that of mouse lines selected for high sensitivity to ethanol-induced hypnosis (79,80). The exact genetic alteration in these BZand eth'anol-sensitive lines remains to be established, with numerous possibilities, including the GABAA receptor system.…”

β‐Lumicolchicine Interacts with the Benzodiazepine Binding Site to Potentiate GABAA Receptor‐Mediated Currents

“…Chloride-36 uptake experiments were performed essentially as described by Allan et al ( 1988). ICR mice (Harlan Sprague Dawley, Indianapolis, IN, U.S.A.) were killed by decapitation and cerebral cortices homogenized by hand (10-12 strokes) in 4.5 ml of assay buffer (containing 145 mM NaCI, 5 mM KCI, 1 mM MgCl,, 1 mM CaCI, , I0 mM mglucose, and 10 mMHEPES, at pH 7.5).…”

“…GABA enhances the binding of BZDs to their receptors (Tallman et al, 1978;Karobath and Sperk, 1979), whereas BZD binding is antagonized by the BZD receptor antagonist flumazenil (Hunkeler et al, 198 1;Taguchi and Kuriyama, 1987). Chloride-36 uptake (Allan et al, 1988;Morrow and Paul, 1988;Obata and Yamamura, 1988;Yu et al, 1988) and electrophysiological (Study and Barker, 1981;Bormann and Clapham, 1985) studies have functionally demonstrated potentiation of GABAA responses by BZDs.…”