Biological research on schizophrenia.

Abstract

Based on the biochemical analysis of postmortem brains from chronic schizophrenic patients, we found abnormalities of glutamatergic neurons as well as dopaminergic neurons. Glutamate receptors, such as the kainate receptor labeled by 3H-kainate, the N-methyl-D-aspartate (NMDA) receptor by 3H MK801, and the strychnine-insensitive glycine sites in the NMDA receptor by 3H-glycine, increased significantly in various cortical areas of schizophrenic brains. According to the animal experiments and a significant negative correlation between kainate binding values and glutamate concentrations, it is suggested that glutamate receptors increased due to hypoglutamatergic function in the brain of chronic schizophrenia. Hyperdopamine hippothesis of schizophrenia is supported by the correlation between affinity to dopamine receptor and clinical potency of antipsychotic drugs. Measurement of tyrosine hydroxylase activity and dopamine D2 receptor in the schizophrenic brain provided evidence of hyperdopaminergia. Association study of a missense variant in the dopamine D2 receptor gene (Cys311) revealed that the allele frequency of the variant was significantly higher in the schizophrenic patients than the controls. The patients carrying this variant had less severe negative symptoms and better response to antipsychotic drug treatment. Dopamine-induced sequestration of dopamine D2S receptor with Cys variant expressed in CHO cells was shown to a lesser extent than wild-type receptor. This experimental result may be consistent with better responsiveness of the patients with Cys311 to antipsychotic drugs.