Biochemical and molecular research on NMDA and GABA ion-channel receptor complexes in animal model for schizophrenia

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The effects of intermittent i.p. administration of cocaine (20 mg/kg) on the picrotoxin sites labeled by [^<35>S] TBPS and alpha1, alpha6, beta2, gamma2 subunit mRNA of GABA_A-BZD receptor complex were investigated by an in vitro quantitative receptor autoradiographic technique and in situ hybridization. Phosphor screen imaging with high sensitivity and wide linear range of response was utilized for autoradiography. Changes in [^<35>S] TBPS binding were examined in 17 brain regions at a concentration of [^<35>S] TBPS of 3nM.Each subunit mRNA was measured in the cerebral cortices, hippocampal formation, accumbens nucleus, ventral pallidum, thalamus and cerebellum.The behavioral changes induced by cocaine injection were manifested more rapidly. The mean scores of stereotyped behavior were increased with the number of injections. There was no significant change in [^<35>S] TBPS binding in the any regions in the brain of rats both 24 hr following a single injection of cocaine and 1 week after the final injection of chronic administrations for 14 days. The cocaine-withdrawal rats 1 week after chronic administration of cocaine showed a significant increase in [^<35>S] TBPS binding in the layr II-III and IV of frontal cortex, and the CA1 region and dentate gyrus of hippocampus. The significant change in each subunit mRNA was revealed only 1 hr after a single injection of cocaine.These findings suggest that the transcriptional factors might affect the turnover of subunit mRNA of GABA_A-BZD receptor complex. In addition, it raises the possibility that GABA_A-BZD receptor complex is closely involved in the development of cocaine withdrawal state.Further studies on the other binding sites in GABA_A-BZD receptor complex would be necessary for an explanation of precise mechanisms undelying the development of hypersensitization and cocaine-induced withdrawal state.