Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions.

TLDR: The results suggest that activation of GAD is an important factor in the mechanism by which several inhibitors of GABA‐T and also valproate increase GABA concentrations in nerve terminals, at least in the relatively non‐toxic doses as used in this study.

Abstract: Five inhibitors of the GABA degrading enzyme GABA-aminotransferase (GABA-T), viz., gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA, ethanolamine O-sulphate, and aminooxyacetic acid, as well as GABA itself and the antiepileptic sodium valproate were administered to mice in doses equieffective to raise the electroconvulsive threshold by 30 V. The animals were killed at the time of maximal anticonvulsant effect of the respective drugs and GABA, GABA-T and glutamate decarboxylase (GAD) were determined in whole brain and synaptosomes, respectively. The synaptosomal fraction was prepared from brain by conventional ultracentrifugation procedures. All drugs studied brought about significant increases in both whole brain and synaptosomal GABA concentrations, and, except GABA itself, inhibited the activity of GABA-T. Furthermore, all drugs, except GABA and gamma-acetylenic GABA, activated GAD in the synaptosomal fraction. This was most pronounced with ethanolamine O-sulphate, which induced a twofold activation of this enzyme but exerted only a weak inhibitory effect on GABA-T. The results suggest that activation of GAD is an important factor in the mechanism by which several inhibitors of GABA-T and also valproate increase GABA concentrations in nerve terminals, at least in the relatively non-toxic doses as used in this study.