Creating and Validating Rat Models for Cognitive Deficits of Schizophrenia

在本研究中，进行了两个实验，以阐明导致精神分裂症基本损害的生物学机制，认知缺陷。首先，我们在大鼠身上复制了精神分裂症认知缺陷的重要证据，P3是反映认知功能的事件相关电位的一个组成部分，其振幅降低和潜伏期延长。第一个实验采用MAP和PCP重复给药模型作为精神分裂症大鼠模型。其次，我们尝试记录新生儿海马损伤大鼠（一种新的精神分裂症大鼠模型）的p3样电位。新生儿海马损伤模型最早是Lipska等通过在大鼠海马腹侧给予伊博tenic酸造成损伤的方法作为精神分裂症动物模型引入的。1)在第一个实验中，雄性SD大鼠被训练来区分两种不同的音调，按下一个反应杠杆，更多地指定音调。通过对内侧前脑束（MFB）的电刺激来促进正确反应，以促进所需的3d辨别学习。在对大鼠进行识别任务训练后，持续产生超过85%命中率的良好表现水平，开始记录p3样电位。大鼠对稀有音调的识别电位与人类的P3电位相似。反复给药后大鼠p3样电位明显减弱。由于MAP和PCP精神病被认为是精神分裂症的模型，反复给药MAP和PCP的大鼠P3样电位降低有望为阐明精神分裂症P3降低的神经化学和神经解剖学基础提供线索。虽然再现了P3波幅降低，但在这些大鼠中没有再现P3潜伏期延长。提示精神分裂症患者P3潜伏期延长的原因与P3波幅降低的原因不同。2)在第二个实验中，新生海马损伤大鼠在出生后56天（PD56）表现出对PCP和MAP的过度行为反应（过度运动），而在出生后35天则没有。PD56为青春期后，pd35为青春期前。这个结果很有趣，因为众所周知，精神分裂症主要发生在青春期之后。该结果提示新生儿精神分裂症海马损伤模型的有效性。采用血透法测定损伤大鼠和假手术大鼠反复给药前后伏隔核内多巴胺（DA）及其代谢物的细胞外浓度。反复给药PCP增加海马损伤大鼠和假手术大鼠DA及其代谢物浓度；然而，假手术大鼠的增加幅度大于损伤大鼠，这与PCP后行为反应的结果不一致。考虑到这些结果，我们认为过度运动的机制不仅包括DA释放增加，还包括由于NMDA受体阻断而导致的gaba能抑制减少，以及仅在细胞内过程中DA系统的信号传递增加。3)新生海马损伤大鼠存在学习困难，双音辨别任务的成绩水平提高明显延迟。当记录损伤大鼠的p3样电位时，它们没有显示出明显的p3样电位。目前，损伤大鼠的p3样电位极弱的原因还有待进一步的研究，特别是需要使用更多的性能水平超过指定标准的损伤大鼠进行研究。少

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