权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Creating and Validating Rat Models for Cognitive Deficits of Schizophrenia

创建并验证精神分裂症认知缺陷的大鼠模型

基本信息

批准号：
08457251
负责人：
NIWA Sin-ichi
金额：
$ 2.37万
依托单位：
Fukushima Medical Univ. School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

In the present study, two experiments were conducted in order to clarify biological mechanisms leading to a fundamental impairment in schizophrenia, cognitive deficit. First, we carried out a trial of replicating in rats a significant evidence for cognitive deficit of schizophrenia, amplitude reduction and latency prolongation of P3 which is a component of event-related potentials reflecting the cognitive function. In the first experiment, repeated MAP administration and PCP administration models were employed as rat models of schizophrenia. Second, we attempted to record P3-like potentials in neonatal hippocampal lesioned rat, a new rat model of schizophrenia. The neonatal hippocampal lesion model was first introduced as an animal model of schizophrenia by Lipska and her colleagues who made lesion by administering the ibotenic acid in the ventral hippocampus of rats.1)In the first experiment, male SD rats were trained to discriminate two different tones pressing a response lever to on … More e designated tone. Electrical stimulation to the medial forebrain bundle(MFB)was delivered to correct responses as rewards to facilitate the require3d discrimination learning. After rats were trained in the discrimination task, constantly yielding good performance levels of more than 85% hit rates, P3-like potentials were begun to be recorded. The rats displayed P3-like potentials to rare tones in the discrimination task markedly similar to human P3 potentials.The P3-like potentials in rats were remarkably attenuated after repeated administration of MAP as well as PCP. Because MAP and PCP psychosis are thought to be models of schizophrenia, the P3-like potential reduction in rats receiving repeated administration of MAP and PCP is expected to provide a clue for elucidating neurochemical and neuroanatomical bases for P3 reduction in schizophrenia. Although P3 amplitude reduction was replicated, P3 latency prolongation was not replicated in these rats. This result may indicate that P3 latency prolongation is caused by different reasons from those for P3 amplitude reduction in schizophrenia.2)In the second experiment, the neonatal hippocampal lesioned rats displayed excessive behavioral responses (hyperlocomotion) to PCP and MAP at the postnatal day 56 (PD56) but not at PD35. PD56 is post-pubertal, while PD 35 is in the pre-pubertal period. This result is intriguing in terms of the well-known fact that schizophrenia mainly starts after puberty. This result indicates the validity of the neonatal hippocampal lesion model of schizophrenia. We measured the extracellular concentrations of dopamine (DA) and its metabolites in the nucleus accumbens (NAc) by means of mycrodialysis from the lesioned and sham-operated rats before and after repeated administration of PCP. Repeated administration of PCP increased DA and its metabolites concentrations in both hippocampal lesioned and sham-operated rats ; however, the extents of increase were greater in the sham-operated rats than the lesioned rats, which was inconsistent with the result for behavioral responses after PCP. Taking these results into account, it is suggested that the mechanisms for hyperlocomotion includes not only increased DA release but also decreased GABAergic inhibition due to NMDA receptor blockade as well ad increased signal transmission in the DA system exclusively at the intracellular processes.3)The neonatal hippocampal lesioned rats had difficulties in learning so that the performance levels for the two-tone discrimination task were markedly delayed in improving. When the P3-like potentials were recorded in the lesioned rats, they failed to display distinct P3-like potentials. At this moment, the reason for extremely attenuated P3-like potentials in the lesioned rats remains to be clarified in further research particularly employing larger number of lesioned rats with exceeding performance levels over the designated criteria. Less

在本研究中，进行了两个实验，以阐明导致精神分裂症的基本损害，认知缺陷的生物学机制。首先，我们进行了一项试验，在大鼠中复制的精神分裂症的认知缺陷，振幅降低和P3的潜伏期延长的一个重要证据，这是一个组成部分的事件相关电位反映的认知功能。在第一个实验中，采用重复MAP给药和PCP给药模型作为精神分裂症大鼠模型。第二，我们尝试在新生的海马损伤大鼠（一种新的精神分裂症大鼠模型）记录P3样电位。新生大鼠海马损伤模型是Lipska等首次引入的精神分裂症动物模型，通过在大鼠腹侧海马给予鹅膏蕈氨酸造成损伤。1）在第一个实验中，训练雄性SD大鼠辨别两种不同的音调，按下一个反应杠杆， ...更多信息 e指定的音调。电刺激内侧前脑束（MFB）以纠正反应作为奖励，以促进所需的3D辨别学习。在对大鼠进行辨别任务训练后，不断产生超过85%命中率的良好表现水平，开始记录P3样电位。大鼠在稀有音调辨别任务中表现出与人类P3电位显着相似的P3样电位，重复给予MAP和PCP后，大鼠的P3样电位显着减弱。由于MAP和PCP精神病被认为是精神分裂症的模型，在大鼠接受重复管理的MAP和PCP的P3样电位降低，预计将提供一个线索，阐明精神分裂症的P3减少的神经化学和神经解剖学基础。虽然P3振幅减少复制，P3潜伏期延长，在这些大鼠中没有复制。实验2）海马损伤大鼠在出生后56天（PD 56）对PCP和MAP表现出过度的行为反应（过度运动），而在PD 35则没有。PD 56是青春期后，而PD 35是青春期前。这个结果很有趣，因为众所周知，精神分裂症主要在青春期后开始。这一结果表明了新生儿海马神经元损伤模型的有效性。用微透析法测定了PCP重复给药前后损毁和假手术大鼠中脑外侧核（NAc）内多巴胺（DA）及其代谢产物的浓度。PCP重复给药后，海马损伤组和假手术组大鼠DA及其代谢产物含量均升高，但假手术组升高幅度大于海马损伤组，这与PCP后行为反应的结果不一致。考虑到这些结果，结果提示，海马损伤后大鼠的过度运动机制不仅包括DA释放增加，而且还包括NMDA受体阻断引起的GABA能抑制减少，以及DA系统的信号传递增加。声调辨别任务的改善明显延迟。当记录到损伤大鼠的P3样电位时，它们不能显示明显的P3样电位。目前，损伤大鼠中P3样电位极度衰减的原因仍有待于进一步研究，特别是采用大量超过指定标准的表现水平的损伤大鼠。少