Elevation of y=Aminobutyric Acid in Brain: Selective Inhibition of y-Aminobutyric-a-ketoglutaric Acid Transaminase*

The quantitative measurement of amino acids in different areas of the central nervous system has shown that a progressive increase takes place in levels of y-aminobutyric acid during development (2, 3), and that the concentration of this amino acid in adult brain is relatively constant under a variety of physiological stresses. y-Aminobutyric acid is synthesized by glutamic acid decarboxylase, an enzyme unique to tissues of the central nervous system (4), and is degraded by y-aminobutyric acid-a-ketoglutaric acid transaminase, which is found also in other tissues of mammals (5). Both of these enzymes require pyridoxal-P as a cofactor (4, 6). It has been shown that, under normal conditions, the level of y -aminobutyric acid in any particular brain area is directly related to levels of maximal potential glutamic acid decarboxylase activity (7), but appears unrelated to levels of y-aminobutyric acid-cr-ketoglutaric acid transaminase.’ The concentration of y-aminobutyric acid in the brains of adult rodents is altered after the intraperitoneal or intravenous injection of a number of compounds (8-14). Among the carbony1 trapping agents are compounds which elevate or depress levels of y-aminobutyric acid. Thiosemicarbazide, injected into rats, lowers levels of y-aminobutyric acid and decreases glutamic acid decarboxylase activity (7), whereas hydroxylamine and aminooxyacetic acid elevate y-aminobutyric acid in the brains of rats (9, 14). The present communication describes some quantitative and temporal details of the interrelationship found between the levels of y-aminobutyric acid, and the activities of the enzymes involved in the synthesis and destruction of this amino acid, when hydroxylamine or aminooxyacetic acid was administered to animals. Results of these experiments, which show that these compounds inhibit y-aminobutyric acid-or-ketoglutaric acid transaminase in brain, are in agreement with the hypothesis that the selective elevation of y-aminobutyric acid in brain tissue after administration of hydroxylamine in viva is the result of a decreased rate of utilization of y-aminobutyric acid by the transaminase reaction at a time when formation by the glutamic acid decarboxylase pathway continues relatively uninterrupted (10).