Bardgett Mark E, Griffith Molly S, Foltz Rebecca F, Hopkins Jessica A, Massie Christina M, O'Connell Shannon M
Department of Psychology, Northern Kentucky University, Highland Heights, KY 41099, USA.
Neurobiol Learn Mem. 2006 Jan;85(1):86-94. doi: 10.1016/j.nlm.2005.08.010. Epub 2005 Oct 6.
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.
氯氮平是一种非典型抗精神病药物，在一些动物模型中已显示出能改善空间记忆；然而，其对海马损伤大鼠空间记忆障碍的逆转效果尚不清楚。为解决这一问题，我们在三个独立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向海马直接立体定向注射兴奋性毒素N-甲基-D-天冬氨酸（NMDA）。在第一项研究中，手术后七天，假手术对照动物每天接受生理盐水注射，而损伤动物被分为两组，分别接受每天生理盐水或氯氮平（2.0毫克/千克，皮下注射）注射。在注射的第五周，所有动物都在以食物为动机的延迟空间交替任务中接受测试。经兴奋性毒素损伤海马并接受生理盐水治疗的大鼠在延迟空间交替方面表现出显著缺陷。每天注射氯氮平完全逆转了这一缺陷。在第二项实验中，发现仅在测试日进行氯氮平治疗并不能改善损伤大鼠的交替表现。最后，在第三项实验中，慢性氯氮平治疗对术前在交替任务中接受过预训练的损伤大鼠的交替表现没有改善作用。这些结果表明，慢性而非急性氯氮平治疗能使海马损伤大鼠发展新的空间学习能力，但无法挽救损伤前建立的旧空间学习能力。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具有启示意义。
