Elevation of γ-aminobutyric acid in brain with amino-oxyacetic acid and susceptibility to convulsive seizures in mice: A quantitative re-evaluation

Abstract

The time courses of changes in brain content of γ-aminobutyric acid (γABA) and sensitivity to electroconvulsive shock were studied in mice after administration of amino-oxyacetic acid (AOAA), an inhibitor of γABA-transaminase. Some correlative observations were made of ATP and glutamate contents and of susceptibility to seizures induced by strychnine, pentylenetetrazole (Metrazol), and picrotoxin. The increase in γABA concentrations as a function of time after AOAA administration (25 mg/kg) was biphasic. A plateau in γABA level was attained between 3 and 4 hr, and a subsequent secondary rise took place between 4 and 6 hr. Elevated values were still observed at the 24-hr period. No changes in ATP content were found after AOAA. There was a remarkable decrease in electroshock seizure incidence (75 mA stimulus) during the first 1·5 hr after AOAA. Subsequently, the susceptibility to seizures began to return to normal, attaining the control values at 6 hr, at which time the γABA content was maximal. Only during the first 1·5-hr period after AOAA was there a good correlation of decrease in seizure susceptibility with increase in γABA content. Similar findings were made on a more limited scale with regard to the parameters measured when chemical convulsants were employed. One of several possibilities suggested by the findings is that the increases in γABA levels and changes in seizure susceptibility after AOAA administration are completely unrelated. Another way to view the results is that soon after γABA-transaminase blockade with AOAA the increased levels of γABA may, indeed, decrease neuronal excitability; however, compensatory increases in excitatory influences or decreases in inhibitory influences other than γABA, or both, may take place with the consequent restoration of normal neuronal sensitivity even during the time when a gross elevation of γABA exists. Glutamic acid, a potentially important excitatory factor in the central nervous system, did not increase after AOAA.