Joy R M, Albertson T E
Department of Pharmacology and Toxicology, School of Veterinary Medicine, University of California, Davis 95616.
Neurotoxicology. 1987 Winter;8(4):517-27.
Rats were anesthetized with urethane, implanted with stimulating and recording electrodes in the perforant path and dentate gyrus, and exposed to different doses of lindane. Analysis of evoked field potential responses indicated that lindane exposure resulted in consistent, dose-dependent changes. Two separable effects were observed. First, lindane produced a small increase in the field excitatory postsynaptic potential (EPSP). Second, lindane produced much more significant effects upon granule cell excitability as evidenced by decreased threshold for evoking the field population spike (PS), increased amplitude of the PS and decreased latencies to PS onset and to peak. An analysis of these data suggests that presynaptic actions, e.g., increased transmitter release from perforant path terminals, do not appear to play an important role in the increased responsivity of granule cells. The most important factor appears to be a dose-dependent increase in the excitability of the granule cell due to other causes. In comparable studies, other subjects were prepared similarly and tested with other convulsive agents. Comparison of lindane to other convulsants revealed that lindane mimicked the changes produced in dentate gyrus responses by GABA antagonist drugs including picrotoxin, pentylenetetrazol and bicuculline. The glycine antagonist, strychnine, produced a different spectrum of effects. The data lend support to the hypothesis that an interaction of lindane with the GABA receptor-chloride channel complex is an important mechanism underlying both subconvulsant and convulsant actions. A reduction in tonic, GABA-mediated inhibition may be the basis for the increase in intrinsic granule cell excitability.
用乌拉坦麻醉大鼠，在穿通通路和齿状回植入刺激电极和记录电极，并使其暴露于不同剂量的林丹。对诱发电场电位反应的分析表明，林丹暴露导致了一致的、剂量依赖性的变化。观察到两种可分离的效应。首先，林丹使场兴奋性突触后电位（EPSP）略有增加。其次，林丹对颗粒细胞兴奋性产生了更为显著的影响，表现为诱发场群体峰电位（PS）的阈值降低、PS的幅度增加以及PS起始和峰值的潜伏期缩短。对这些数据的分析表明，突触前作用，例如穿通通路终末递质释放增加，似乎在颗粒细胞反应性增加中不起重要作用。最重要的因素似乎是由于其他原因导致颗粒细胞兴奋性的剂量依赖性增加。在类似的研究中，其他实验对象也进行了类似的准备，并使用其他惊厥剂进行测试。将林丹与其他惊厥剂进行比较发现，林丹模拟了包括印防己毒素、戊四氮和荷包牡丹碱在内的GABA拮抗剂药物在齿状回反应中产生的变化。甘氨酸拮抗剂士的宁产生了不同的效应谱。这些数据支持了这样一种假说，即林丹与GABA受体-氯离子通道复合物的相互作用是亚惊厥和惊厥作用的重要潜在机制。GABA介导的紧张性抑制的降低可能是颗粒细胞内在兴奋性增加的基础。
