Tandon P, Barone S, Drust E G, Tilson H A
Laboratory of Molecular and Integrative Neuroscience, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Neurotoxicology. 1991 Spring;12(1):67-77.
Previous work in our laboratory has shown that the intradentate administration of colchicine produces time-dependent behavioral and neurochemical changes. Deficits in learning and memory and alterations in the signal transduction process for the cholinergic muscarinic receptor have been observed up to 12 weeks after colchicine treatment. To study the long-term effects of colchicine administration on cognitive function and the cholinergic system, 6 month-old male, Fischer-344 rats were injected with 2.5 micrograms of colchicine bilaterally in the dorsal and ventral hippocampus. Twelve months later the animals were tested for the acquisition of a spatial reference memory task in the Morris water maze for 8 days, with 4 trials of 60 seconds each day. At the completion of the behavioral testing, one set of rats from each treatment group was used for histochemical studies. The remaining animals were sacrificed, the hippocampi removed and used for the estimation of receptor-stimulated turnover of phosphoinositides (Pl). [3H]-inositol was incorporated into the hippocampal slices, and various receptor agonists (carbachol, norepinephrine, serotonin) used to stimulate Pl turnover in the presence of lithium. A significant deficit in acquisition in the water maze was observed in animals 1 year after colchicine administration. Neurochemical studies showed an increase in carbachol-induced Pl metabolism in the rat hippocampus 1 year post-lesion with colchicine. However, in contrast to results obtained 12 weeks after lesioning, no significant changes were observed in norepinephrine or serotonin-induced Pl metabolism 1 year after lesioning. Pirenzepine, a M1 receptor antagonist, produced a greater degree of inhibition (62%) in lesioned animals as compared to the age-matched controls (20%). Increased staining for acetylcholinesterase was found in the hippocampus of treated rats. This effect is similar to that observed 12 weeks after lesioning. These data suggest that the effects of colchicine on the cholinergic system are long-lasting and can be observed a year after treatment.
我们实验室之前的研究表明，向齿状体内注射秋水仙碱会产生时间依赖性的行为和神经化学变化。在秋水仙碱治疗后长达12周，观察到学习和记忆缺陷以及胆碱能毒蕈碱受体信号转导过程的改变。为了研究秋水仙碱给药对认知功能和胆碱能系统的长期影响，给6个月大的雄性Fischer-344大鼠双侧海马背侧和腹侧注射2.5微克秋水仙碱。12个月后，对动物进行为期8天的莫里斯水迷宫空间参考记忆任务习得测试，每天进行4次每次60秒的试验。行为测试完成后，每个治疗组的一组大鼠用于组织化学研究。其余动物被处死，取出海马用于评估受体刺激的磷酸肌醇（Pl）周转。将[3H]-肌醇掺入海马切片中，并使用各种受体激动剂（卡巴胆碱、去甲肾上腺素、5-羟色胺）在锂存在的情况下刺激Pl周转。在秋水仙碱给药1年后的动物中，观察到水迷宫习得存在显著缺陷。神经化学研究表明，秋水仙碱损伤后1年，大鼠海马中卡巴胆碱诱导的Pl代谢增加。然而，与损伤后12周获得的结果相反，损伤后1年去甲肾上腺素或5-羟色胺诱导的Pl代谢未观察到显著变化。与年龄匹配的对照组（20%）相比，M1受体拮抗剂哌仑西平在损伤动物中产生了更大程度的抑制（62%）。在治疗大鼠的海马中发现乙酰胆碱酯酶染色增加。这种效应与损伤后12周观察到的效应相似。这些数据表明，秋水仙碱对胆碱能系统的影响是持久的，并且在治疗1年后仍可观察到。
