METABOLIC PRECURSORS AND COMPARTMENTATION OF CEREBRAL GABA IN VIGABATRIN-TREATED RATS

The metabolic precursors and cerebral compartmentation of the augmente d GABA pool induced by vigabatrin, an irreversible inhibitor of GABA t ransaminase, have been investigated by C-13 NMR. Adult rats receiving rat chow ad libitum were given either drinking water only or drinking water containing 2.5 g/L vigabatrin for 7 days. Both groups of animals were infused either with [1,2-C-13(2)]acetate (15 mu mol/min/100 g bo dy weight), an exclusive precursor of GABA formation through the glial glutamine pathway, or with [1,2-C-13(2)]glucose (15 mu mol/min/100 g body weight), a substrate that can produce GABA through the glial glut amine pathway or by direct metabolism in the neurons. The brains were frozen in situ, extracted with perchloric acid, and analyzed by C-13 N MR. In vigabatrin-treated animals [C-13]glutamine, a common intermedia te for [C-13]GABA synthesis from glucose or acetate, was accumulated t o similar amounts during infusions with [1,2-C-13(2)]glucose or [1,2-C -13(2)]acetate. However, [C-13]GABA accumulation was sevenfold higher during [1,2-C-13(2)]glucose infusions or twofold higher during [1,2-C- 13(2)]acetate infusions. These results show that the direct pathway of GABA formation by neuronal metabolism of glucose predominates over th e alternative pathway through glial glutamine. Near-equilibrium relati onships of the aminotransferases of GABA and aspartate imply that the observed [C-13]GABA accumulation occurs initially in the neuronal comp artment.