Getova D, Froestl W, Bowery N G
Department of Pharmacology and Toxicology, Higher Medical School Plovdiv, Bulgaria.
Brain Res. 1998 Nov 2;809(2):182-8. doi: 10.1016/s0006-8993(98)00864-6.
Pentylenetetrazol (PTZ) administered chronically in rodents induces kindling which is considered to be a model of chronic epilepsy mediated through a specific interaction with the GABA-gated chloride ionophore. PTZ kindling also impairs shuttle-box learning indicating a possible modulation of memory storage [A. Becker, G. Grecksch, H. Mathies. The influence of diazepam on learning processes impaired by pentylenetetrazol kindling. Naunyn-Schmiedeberg's Arch. Pharmacol. 349 (1994) 429-496]. Since GABAB receptor antagonism has been shown to improve cognitive performance in rodents and primates we have examined the effects of 3 antagonists; CGP 36742 (3-amino-propyl-n-butyl-phosphinic acid), CGP 56433 ([3-¿1-(S)-[¿3-(cyclohexylmethyl) hydroxyphosphinyl]-2-(S)-hydroxypropyl]-amino]ethyl]benzoic acid) and CGP 61334 ([3-¿[3[(diethoxymethyl)hydroxyphosphinyl]-propyl-amino¿meth yl]-benzoic acid) on the induction of PTZ kindling in mice at 48 h intervals for 8 weeks. Subsequently the mice were tested in an active avoidance paradigm. At the end of the experiment GABAB receptor autoradiography was performed on brain sections from these animals. Seizure intensity increased progressively in control mice reaching by 8 weeks a mean score which corresponded to clonic seizures. The GABAB antagonists suppressed kindling during the first 4 weeks and after that restored the seizure intensity to the level of control animals. The level of kindling was proportional to the avoidance score. The density of GABAB receptor binding in brain sections from PTZ kindled mice was significantly greater than in controls. This was not altered by pretreatment with the GABAB antagonists except in the cerebellum.
长期给啮齿动物注射五甲烯四氮唑（PTZ）会引发点燃效应，这被认为是一种慢性癫痫模型，其通过与GABA门控氯离子通道蛋白的特定相互作用介导。PTZ点燃效应还损害穿梭箱学习，表明可能对记忆存储有调节作用[A. 贝克尔、G. 格雷克斯、H. 马西斯。地西泮对五甲烯四氮唑点燃效应损害的学习过程的影响。《瑙尼-施密德贝格药理学文献》349（1994）429 - 496]。由于已证明GABAB受体拮抗作用可改善啮齿动物和灵长类动物的认知表现，我们研究了3种拮抗剂；CGP 36742（3 - 氨基丙基 - n - 丁基 - 次膦酸）、CGP 56433（[3 - {[1 - (S)-[3 - (环己基甲基)羟基膦酰基]-2 - (S)-羟丙基] - 氨基}乙基]苯甲酸）和CGP 61334（[3 - {[3[(二乙氧基甲基)羟基膦酰基] - 丙基 - 氨基}甲基] - 苯甲酸）对小鼠PTZ点燃效应诱导的影响，每隔48小时给药一次，持续8周。随后对小鼠进行主动回避范式测试。实验结束时，对这些动物的脑切片进行GABAB受体放射自显影。对照小鼠的癫痫发作强度逐渐增加，到8周时达到与阵挛性发作相对应的平均评分。GABAB拮抗剂在最初4周抑制点燃效应，之后将癫痫发作强度恢复到对照动物的水平。点燃程度与回避评分成正比。PTZ点燃小鼠脑切片中GABAB受体结合密度显著高于对照小鼠。除小脑外，GABAB拮抗剂预处理对此无改变。
