The Study of Cholinergic Nerve Disfunction induced by AF64A.

全身毒性：大鼠腹腔注射。AF64A剂量为1/3~11/25时，LD50(291umol/kg)表现为一过性运动障碍和持久的失脂、失神症状。大鼠腹腔注射AF64A，起始剂量为86umol/kg。连续9天给药12.9umol/kg，大脑皮层、海马区和纹状体ACh含量显著降低。即使在最后一次注射后10天，这种下降仍然持续。电刺激或高K^引起的ACh释放明显减少。治疗组大鼠的T迷宫自发交替行为也受到损害。其他神经递质如去甲肾上腺素、5-羟色胺和GABA水平无变化。神经化学观察：给予胆碱和AF64A可明显抑制大鼠中枢胆碱能神经系统功能缺陷体征的发展。在AF6…中4A处理组大鼠海马区和大脑皮层神经末梢的ChAT活性降低，而药物对提取的可溶性ChAT无直接影响。AF64A处理的大鼠脑突触小体具有与对照组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。应用：在AF64A治疗的小鼠中，狄氏剂诱发的神经毒性症状明显减轻，支持了我们先前提出的中枢兴奋性胆碱能机制可能参与神经毒性症状的说法。在另一系列实验中，AF64A处理的大鼠有一半的肠道未能在局部扩张的肠壁的肛门部产生环状肌肉的松弛。结论：AF64A是研究胆碱能神经系统生理作用的一种有用的试剂。较少

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