The Study of Cholinergic Nerve Disfunction induced by AF64A.

全身毒性：以1/3至11/25 LD 50（291 umol/kg）的剂量腹腔注射AF 64 A的大鼠显示短暂的运动障碍体征和持久的厌食和吞咽障碍体征。大鼠腹腔注射AF 64 A（起始剂量86 μ mol/kg，连续9天，剂量为12.9 μ mol/kg）后，大脑皮层、海马和纹状体ACh含量显著降低。即使在最后一次注射后10天，这种下降也持续存在。由电刺激或高K^+诱导的ACh释放显著减少。给药组大鼠的T-迷宫自发交替行为也受到损害。其他神经递质如NE、5-HT和GABA的水平无变化。神经化学观察结果：给予胆碱和AF 64 A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AF 6 ...更多信息 4A处理组大鼠海马和皮层神经末梢ChAT活性降低，而对提取的可溶性ChAT无直接影响。AF 64 A处理的大鼠脑突触体制备物具有与对照相同的高亲和力胆碱摄取活性。[^3H]尼古丁与皮层膜的特异性结合增强。这些结果进一步支持突触前位点的aciton为AF 64 A，并表明，它可能会严重破坏一些过程的基础ACh release.Applications：在AF 64 A治疗的小鼠，狄氏剂引起的神经毒性症状明显减轻支持我们以前的建议，中枢神经系统兴奋性胆碱能机制可能参与的神经毒性症状。在另一系列实验中，来自AF 64 A治疗的大鼠的一半肠不能产生局部扩张的肠壁的肛门部分中的环形肌肉的松弛。结论：AF 64 A是研究胆碱能神经系统生理功能的有效药物。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