Allan A M, Gallaher E J, Gionet S E, Harris R A
Research Service, VA Medical Center, Denver, CO 80262.
Brain Res. 1988 Jun 14;452(1-2):118-26. doi: 10.1016/0006-8993(88)90016-9.
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)
在对安定的共济失调作用具有不同敏感性的小鼠（安定敏感（DS）系和安定抵抗（DR）系）中，评估了γ-氨基丁酸（GABA）受体操纵的氯离子通道复合物。使用转棒试验检测了几种据称通过苯二氮卓-GABA受体复合物发挥部分作用的药物的共济失调作用。安定、乙醇、4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇（THIP）和苯巴比妥产生的损伤持续时间在安定敏感小鼠中比在安定抵抗小鼠中更长。相比之下，戊巴比妥在两系小鼠中产生的共济失调持续时间相同。使用分离的脑膜囊泡（微囊）测量了蝇蕈醇刺激的36Cl-内流以及[35S]叔丁基双环磷硫代酸盐（TBPS）和[3H]氟硝西泮的结合。在全脑突触体中测量了去极化依赖性45Ca2+摄取。与DR小鼠相比，蝇蕈醇在DS小鼠中是更有效的36Cl-通量刺激剂，尽管在蝇蕈醇刺激的[3H]氟硝西泮结合方面两系之间未发现差异。氟硝西泮增强了DS小鼠中蝇蕈醇刺激的36Cl-摄取，但在DR小鼠中未增强。然而，在小鼠品系之间，[3H]氟硝西泮结合位点的密度或亲和力均未发现差异。同样，[35S]TBPS结合位点的密度或亲和力也未发现差异。乙醇（10-45 mM）增强了DS小鼠中蝇蕈醇对36Cl-的刺激，对DR小鼠无影响。然而，乙醇对[35S]TBPS结合的抑制在两系小鼠中相同。戊巴比妥在两系中对蝇蕈醇刺激的36Cl-通量产生同等增强作用，但苯巴比妥在DS小鼠中对蝇蕈醇诱导的36Cl-内流的增强作用略大。（摘要截于250字）
