Creating and Validating Rat Models for Cognitive Deficits of Schizophrenia

在本研究中，为了阐明导致精神分裂症一种根本损害--认知缺陷的生物学机制，本研究进行了两个实验。首先，我们在大鼠身上复制了精神分裂症认知缺陷的显著证据，P3的波幅降低和潜伏期延长，P3是反映认知功能的事件相关电位的一个组成部分。实验一采用MAP重复给药和PCP给药模型作为精神分裂症大鼠模型。其次，我们尝试记录新生的精神分裂症大鼠模型--新生海马区损毁大鼠的P3样电位。新生大鼠海马区损伤模型是由Lipska和她的同事首先引入的一种精神分裂症的动物模型，他们通过在大鼠的腹侧海马区注射鹅膏巴比妥酸造成损伤。1)在第一个实验中，雄性SD大鼠被训练区分两种不同的音调，按下…上的反应杠杆更多的是指定的音调。给予内侧前脑束(MFB)电刺激以获得正确的反应作为奖励，以促进所需的3d辨别学习。大鼠在进行辨别任务训练后，不断产生85%以上的良好操作水平，开始记录到类P3电位。在辨别任务中，大鼠对稀有音表现出类似P3的电位，与人的P3电位非常相似。反复给予MAP和PCP后，大鼠的类P3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，重复给予MAP和PCP的大鼠的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。虽然这些大鼠的P3波幅降低，但P3潜伏期的延长并未在这些大鼠中复制。这一结果可能表明，P3潜伏期延长与精神分裂症P3波幅降低的原因不同。2)在第二次实验中，新生大鼠在出生后56天(PD56)表现出对PCP和MAP的过度行为反应(多动)，而在PD35天则没有。PD56处于青春期后，而PD 35处于青春期前。这一结果很耐人寻味，因为众所周知的事实是，精神分裂症主要始于青春期之后。这一结果表明了精神分裂症新生大鼠海马区病变模型的有效性。用肌透析法测定反复给予PCP前后损毁大鼠和假手术大鼠伏核(NAC)内多巴胺(DA)及其代谢物的胞外浓度。反复给予PCP可使损毁大鼠和假手术大鼠海马多巴胺及其代谢物浓度升高，但假手术大鼠升高幅度大于损毁大鼠，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，超运动的机制不仅包括增加DA的释放，还包括减少由于NMDA受体阻断引起的GABA能抑制，以及增加DA系统中仅限于细胞内过程的信号传递。3)新生大鼠学习困难，导致双音辨别任务的成绩水平明显延迟提高。当在损毁大鼠中记录到类P3电位时，它们不能显示出明显的类P3电位。目前，损毁大鼠P3样电位极度减弱的原因仍有待进一步研究，特别是使用超过指定标准的大量损毁大鼠。较少

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