Joy R M, Albertson T E
Department of Veterinary Pharmacology and Toxicology, School of Veterinary Medicine, University of California, Davis 95616.
J Pharmacol Exp Ther. 1988 Sep;246(3):887-95.
The dentate gyrus of intact urethane-anesthetized rats was employed to evaluate the effects of different convulsive agents on granule cell excitability. One purpose of this study was to determine whether mechanisms of action suggested from in vitro studies of these compounds could be demonstrated over clinically relevant dose ranges in vivo. The data demonstrate that drugs capable of antagonizing gamma amino butyric acid (GABA)-mediated inhibition produced similar effects on the intact hippocampus. Bicuculline, picrotoxin, pentylenetetrazol and the insecticide lindane increased granule cell excitability to perforant path stimulation. The primary cause of this was an increase in the innate excitability of the granule cells. These compounds also modified field potentials in a manner consistent with a reduction in early GABA-mediated inhibition. They did not affect synaptically mediated facilitation. The magnitudes of the effects were dose dependent, and changes were clearly measurable at exposures that produce clinical effects in nonanesthetized rats. Other convulsants could be readily differentiated from those affecting GABA-mediated inhibition. Kainic acid depressed granule cell responses to perforant path stimulation and severely depressed both inhibition and facilitation. A decrease in granule cell responsiveness was also produced by exposure to beta carboline. Exposure to strychnine had little effect on granule cell excitability. These data indicate that for bicuculline, picrotoxin, pentylenetetrazol and lindane, an apparently selective antagonism of GABA-mediated inhibition is clearly demonstrable at exposures that also produce clinical intoxication.(ABSTRACT TRUNCATED AT 250 WORDS)
利用完整的经氨基甲酸乙酯麻醉的大鼠的齿状回，评估不同惊厥剂对颗粒细胞兴奋性的影响。本研究的一个目的是确定从这些化合物的体外研究中提出的作用机制在体内临床相关剂量范围内是否能够得到证实。数据表明，能够拮抗γ-氨基丁酸（GABA）介导的抑制作用的药物对完整的海马体产生相似的影响。荷包牡丹碱、印防己毒素、戊四氮和杀虫剂林丹增加了颗粒细胞对穿通通路刺激的兴奋性。其主要原因是颗粒细胞固有兴奋性的增加。这些化合物还以与早期GABA介导的抑制作用减弱相一致的方式改变了场电位。它们不影响突触介导的易化作用。效应的大小呈剂量依赖性，在能使未麻醉大鼠产生临床效应的暴露剂量下，变化清晰可测。其他惊厥剂可以很容易地与那些影响GABA介导的抑制作用的惊厥剂区分开来。 kainic酸抑制颗粒细胞对穿通通路刺激的反应，并严重抑制抑制作用和易化作用。暴露于β-咔啉也会导致颗粒细胞反应性降低。暴露于士的宁对颗粒细胞兴奋性影响很小。这些数据表明，对于荷包牡丹碱、印防己毒素、戊四氮和林丹，在产生临床中毒的暴露剂量下，明显的GABA介导的抑制作用选择性拮抗作用清晰可证。（摘要截短为250字）
