The Study of Cholinergic Nerve Disfunction induced by AF64A.

一般毒性：大鼠腹腔注射使用剂量为 1/3 至 11/25 LD50 (291 umol/kg) 的 AF64A 表现出短暂的运动障碍症状以及持久的口渴和食欲不振症状。当大鼠腹腔注射初始剂量为 86 umol/kg 的 AF64A 时。连续九日剂量12.9umol/kg，大脑皮层、海马和纹状体中ACh含量显着下降。即使在最后一次注射后 10 天，这种下降仍然持续。由电刺激或高K^诱导的ACh释放显着减少。接受治疗的大鼠的 T 迷宫自发交替行为也受到损害。其他神经递质如 NE、5-HT 和 GABA 的水平没有变化。光镜或电镜观察未发现大脑形态发生变化。神经化学观察：胆碱与AF64A联合给药可显着抑制大鼠中枢胆碱能神经系统功能缺陷症状的发展。在 AF6 … More 4A 治疗的大鼠中，海马和皮层神经末梢 ChAT 活性下降，而该试剂对提取的可溶性 ChAT 没有直接影响。 AF64A处理大鼠的脑突触体制品具有与对照相同的高亲和力胆碱摄取活性。 [^3H]尼古丁与皮质膜制剂的特异性结合增加。这些结果进一步支持了 AF64A 的突触前位点，并表明它可能会严重破坏乙酰胆碱释放的一些过程。 应用：在 AF64A 治疗的小鼠中，狄氏剂引起的神经毒性症状明显减轻，支持了我们之前的观点，即中枢神经系统中的兴奋性胆碱能机制可能与神经毒性症状有关。在另一系列实验中，AF64A治疗大鼠的一半肠道未能使局部扩张的肠壁肛门部分的环形肌产生松弛。这些结果表明从机械感受器到平滑肌的神经通路中存在胆碱能中间神经元。结论：AF64A是研究胆碱能神经系统生理作用的有用药物。较少的

General toxicity:Rat injected i.p. with AF64A at a dose of 1/3 to 11/25 LD50 (291 umol/kg) showed a transient sign of motor disterbance and long lasting singns of adipsia and aghagia. When rats received AF64A with an initial dose of 86 umol/kg i.p. and nine consecutive daily dose of 12.9 umol/kg, ACh contents in the cerebral cortex, hippocampus and striatum decreased significantly. The decrease was sustained even 10 days after the last injection. ACh release induced by electrical stimulation or high K^+ was significantly reduced. The T-maze spontaneous alternation behavior in the treated rats was also impaired. The levels of other neurotransmitters such as NE, 5-HT and GABA were unchanged. No morphological changes in the brain was detected by light- or electron-microscopic observations.Neurochemical observations:Administration of choline with AF64A significantly inhibited the development of the signs of the functional deficienty of central cholinergic nervous system in rats. In the AF6 … More 4A treated rats, ChAT activity in nerve terminals decreased in hippocampus and cortex, while the agent had no direct effect on the extracted soluble ChAT. The brain synaptosomal preparations from AF64A treated rat had the same activity of high affnity choline uptake with that of control. A specific binding of [^3H]nicotine to membrane preparation from cortex increases. These results further support a presynaptic site of aciton for AF64A, and suggest that it may acutely disrupt some processes underlying ACh release.Applications:In AF64A treated mice, the neurotoxic symptoms evoked by dieldrin were clearly alleviated supporting our previous suggestion that excitatory cholinergic mechanism in CNS may be involved in the neurotoxic symptoms. In another series of experiments, half of intestines form AF64A treated rats failed to produce the relaxations of the circular muscles in the anal part of locally distended wall of the intestine. These results suggest that there exist cholinergic interneurons in the nervous pathways from the mechano-receptors to the smooth muscles.Conclusion: AF64A is an usuful agent in studying the physiological roles of cholinergic nervous systems. Less