The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage
The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage
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DOI：
10.1016/j.nlm.2005.08.010
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发表时间：
2006-01-01
影响因子：
2.7
通讯作者：
O'Connell, SM
中科院分区：
文献类型：
--
作者：
Bardgett, ME;Griffith, MS;O'Connell, SM
氯氮平是一种非典型的抗精神病药物，在一些动物模型中已被证明可以改善空间记忆;但其在逆转海马损伤大鼠空间记忆障碍方面的疗效尚不清楚。为了解决这个问题，我们在三个独立的实验中测试了氯氮平对海马损伤大鼠延迟空间交替缺陷的影响。在每个实验中，成年雄性大鼠接受假手术或直接立体定位注入兴奋毒素，NMDA，到海马。在第一项研究中，手术后7天，假手术对照组动物每天接受生理盐水注射，而损伤组动物分为两组，每天接受生理盐水或氯氮平（2.0 mg/kg，sc）注射。在注射的第五周期间，所有动物在食物驱动的延迟空间交替任务中进行测试。生理盐水处理的大鼠兴奋性海马损伤表现出显着的缺陷，在延迟空间交替。每天注射氯氮平完全逆转了这种缺陷。在第二个实验中，发现仅限于测试日的氯氮平治疗并不能改善受损大鼠的交替表现。最后，在第三个实验中，慢性氯氮平治疗并没有改善手术前在交替任务中预先训练的受损大鼠的交替性能。这些结果表明，慢性，而不是急性，氯氮平治疗，使大鼠海马。损伤可以发展新的空间学习，但不能挽救损伤前建立的旧的空间学习。这些结果可能对治疗精神分裂症、阿尔茨海默病等疾病中海马功能障碍引起的认知缺陷有意义。(c)2005年爱思唯尔公司All rights reserved.
Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal. damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others. (c) 2005 Elsevier Inc. All rights reserved.