|Budget Amount *help
¥3,700,000 (Direct Cost : ¥3,700,000)
Fiscal Year 1998 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1997 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1996 : ¥2,700,000 (Direct Cost : ¥2,700,000)
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
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