| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1993: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1992: ¥900,000 (Direct Cost: ¥900,000)
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| Research Abstract |
Experiments were performed to examine nuerochemically the functional diversity of GABA_A receptors as measured by muscimol-, 5alpha-pregnane-3alpha, 21-diol-20-one (THDOC)-, and pentobarbital-stimulated ^<36>Cl^- uptake, and region-specific changes in muscimol- and THDOC-stimulated ^<36>Cl^- uptake in rats treated acutely or subacutely with a subconvulsive dose of bicuculline. The data for stimulation of ^<36>Cl^- uptake by muscimol showed a single binding site interaction in the cerebral cortex, hippocampus and cerebellum. The concentration-response curves for muscimol in the cerebral cortex and hippocampus were steep and indicated an increase of approximately 130% at the maximum concentration. In contrast, the curve for the cerebellum was shallow and exhibited a smaller maximal response (-60%. Apparent affinity for muscimol also differed among these brain regions. Although the concentration-response curves for THDOC did not fit a single-site model for the cerebral cortex and hippocam
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pus, the curve for the cerebellum was monophasic.
There were no differences in the maximal stimulation induced by THDOC among the regions tested. The regional differences in ^<36>Cl^- uptake induced by pentobarbital were not as apparent as those induced by muscimol ; however, the maximal modulatory effect in the hippocampus was significantly higher than that in the cerebellum. In rats treated subacutely with a subconvulsive does of bicuculline, a significant increase in muscimol-stimulated ^<36>Cl^- uptake was observed in the cerebellum but not in the frontal cortex or hippocampus. Analysis of the concentration-response curves for muscimol-stimulated ^<36>Cl^- uptake in the cerebellum revealed that the Vmax for muscimol in the subacutely treated group was significantly higher than those for muscimol in the control and acutely treated groups without any differences in the Kd value.
In addition, muscimol-stimulated ^<36>Cl^- uptake in the hippocampus of the acutely treated group was significantly higher than those in the control group. These results suggest that regional variation of ^<36>Cl^- uptake stimulated by muscimol is more apparent than those stimulated by THDOC and pentobarbital. The present results, along with our previous findings, also indicate that bicuculline up-regulation of GABA_A receptors in the cerebellum involves not only an increase in the density of the receptors as measured by binding assay, but also an increase of ^<36>Cl^- uptake mediated through GABA recognition sites. Less
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