Molecular genetic and experimental studies on abnormalities of glutamatergic transmission in schizophrenia

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Following studies were undertaken to investigate the pathophysiology underlying abnormalities of glutamatergic transmission in schizophrenia. First, a molecular genetic abnormality in gene encoding N-acetylated alpha-linked acidic dipeptidase (NAALADase) was investigated in patients with schizophrenia. Second, experimental studies were performed using several possible animal models of schizophrenia. Rats administered with antisense oligonucleotide complementary to mRNA of NAALADase into the bilateral entorhinal cortex did not show changes in spontaneous locomotor activity or metamphetamine-induced locomotor activity. Intracerebroventricular administration to rats with antisense oligonucleotide complementary to mRNA of N-methyl-D aspartate (NMDA) R1 subunit induced a significant reduction in dopamine D2 receptor density in the substantia nigra using in vitro [3H] YM-09151-2 autoradiography as well as a significant increase in dopamine D2 mRNA in the striatum using northern blot analysis. In rats treated chronically with non-competitive NMDA antagonist, phencyclidine or MK-801, behaviors related social interaction were significantly decreased.