Lipska B K, Weinberger D R
Clinical Brain Disorders Branch, National Institute of Mental Health, NIH, Washington, DC 20032.
Neuropsychopharmacology. 1994 May;10(3):199-205. doi: 10.1038/npp.1994.22.
We have previously demonstrated that rats with neonatal excitotoxic hippocampal damage manifest abnormal dopamine (DA)-related behaviors after puberty, a phenomenon that has implications for an animal model of schizophrenia. In this study we investigated the effects of subchronic treatment with haloperidol and clozapine in these animals. The ventral hippocampus (VH) of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). Starting at PD56, rats were treated for 21 days with either vehicle (VEH), haloperidol (HAL) (0.1 mg/kg, IP), or clozapine (CLOZ) (4 mg/kg, IP). Spontaneous locomotor activity was measured 0.5 hour after the last injection. Apomorphine (APO)-induced stereotypy and locomotion were evaluated five days later. The VH lesioned rats treated with VEH expressed enhanced novelty- and apomorphine-induced hyperlocomotion, as well as potentiated apomorphine-induced stereotypic behaviors as compared to sham-lesioned counterparts. Spontaneous locomotor activity was suppressed by haloperidol but not by clozapine in the sham-operated group, whereas both drugs were effective in suppressing hyperlocomotion in the VH lesioned rats. Withdrawal supersensitivity to apomorphine was seen in the haloperidol but not in the clozapine-treated lesioned rats, and none of the drugs produced significant supersensitivity in the sham-operated animals. These results indicate that the two neuroleptics exerted differential behavioral effects in neurologically intact and hippocampally lesioned animals, and that these effects were also drug-specific.
我们之前已经证明，新生期遭受兴奋性毒性海马损伤的大鼠在青春期后会表现出与多巴胺（DA）相关的异常行为，这一现象对精神分裂症动物模型具有重要意义。在本研究中，我们调查了氟哌啶醇和氯氮平对这些动物进行亚慢性治疗的效果。在出生后第7天（PD7），用鹅膏蕈氨酸损伤大鼠幼崽的腹侧海马（VH）。从PD56开始，大鼠用溶剂（VEH）、氟哌啶醇（HAL）（0.1mg/kg，腹腔注射）或氯氮平（CLOZ）（4mg/kg，腹腔注射）治疗21天。在最后一次注射后0.5小时测量自发运动活性。五天后评估阿扑吗啡（APO）诱导的刻板行为和运动。与假损伤对照组相比，接受VEH治疗的VH损伤大鼠表现出增强的新奇性和阿扑吗啡诱导的运动亢进，以及增强的阿扑吗啡诱导的刻板行为。在假手术组中，氟哌啶醇抑制自发运动活性，但氯氮平无此作用，而两种药物在VH损伤大鼠中均能有效抑制运动亢进。氟哌啶醇治疗的损伤大鼠出现对阿扑吗啡的撤药超敏反应，而氯氮平治疗的损伤大鼠未出现，且在假手术动物中，没有一种药物产生明显的超敏反应。这些结果表明，两种抗精神病药物在神经功能完整和海马损伤的动物中产生了不同的行为效应，且这些效应也是药物特异性的。
