Free amino acids and glutamate decarboxylase activity in brain of mice during drug-induced convulsions

Abstract

Previous administration of l-glutamic acid-γ-hydrazide (GAH) to mice did not protect them against the convulsant action of thiosemicarbazide, methionine sulfoximine, insulin, or pentylenetetrazol (Metrazol). The concentrations of some free amino acids were measured in the brains from these mice at the moment of convulsions. The changes in free amino acid concentrations produced by the convulsant agents used were in general similar whether GAH had been administered or not. In the first case, however, the changes were exerted on the altered pattern of amino acids obtained by the previous GAH treatment. In all cases when GAH and the convulsant agent were injected and convulsions were produced, a two- to four-fold increase of γ-aminobutyric acid (GABA) concentration was found in brain. In other experiments, it was found that GAH administration increased both free and bound GABA concentrations. When a single convulsant dose of GAH was injected, brain glutamate decarboxylase activity progressively decreased with time. The maximal glutamate decarboxylase inhibition was observed at the onset of convulsions; at this moment GABA levels were increased. γ-Aminobutyric aminotransferase activity was diminished more intensely before the onset than at the occurrence of the convulsive state. Similarly, after the injection of a convulsant dose of amino-oxyacetic acid, glutamate decarboxylase activity was decreased at the onset of convulsions, whereas γ-aminobutyric transferase activity was totally inhibited; GABA levels were significantly increased. Anticonvulsant doses of amino-oxyacetic acid protected mice against convulsions induced by the simultaneous administration of GAH and pyridoxal phosphate. Glutamate decarboxylase activity was found equally diminished in protected and in nonprotected mice in comparison with control animals. It is concluded that the inhibition of glutamate decarboxylase activity, independently of the total concentration of GABA in brain, may be a factor involved in the production of some types of convulsions, and probably the anticonvulsant action of amino-oxyactic acid is not related to its effect on GABA metabolism in brain.