| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
Neonatal ventral hippocampal (nVH) damaged rat models, based on the neurodevelopmental disorder hypothesis of schizophrenia, have recently been shown to share many similarities with schizophrenia (e.g. susceptibility to stress, dopaminergic hypersensitivity, and postpubertal onset). We recently reported that this animal model showed hyperresponsiveness not only to methamphetamine (MAP), but also to phencyclidine (PCP), and this model does not depend on the extracellular concentration of dopamine in the nucleus accumbens, and glycine (GLY) which acts as a co-agonist of N-methyl-D-aspartate (NMDA) receptor reduced MAP-induced hyperlocomotion in nVH damaged rats. From these findings, it is possible that this animal model may include the functional abnormalities both of dopaminergic- and of glutamatergic-systems after puberty, and the improvement of the glutamatergic dysfunction may have therapeutic effects. In the present study, we investigated whether the chronic treatment with GLY and D-serine reduce hyperactivity in adolescence. Analysis of total distance traveled showed that, under all testing conditions, sham and lesioned rats were similar at PD35 (as juveniles). At PD56 (in adolescence), Lesion rats were more active than sham operates at habituation, after methamphetamine (we and others have shown). Each Lesion-GLY and Lesion-D-serine rats, pretreated with GLY(1mM) or D-serine(1mM) for 14 days, significantly reduced locomotor activity compared with Lesion-control rats at PD56. The novel finding of the present study was that the continuous treatment of GLY and D-serine reduced nVH-induced hyperactivity (corresponding to positive symptoms of schizophrenia) in nVH damaged rats, and this effect was evident both in the presence and absence of MAR These findings support the hypoglutamatergic hypothesis of schizophrenia, and raise the possibility that GLY and D-serine therapy could improve positive symptoms in patients with schizophrenia.
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