Brain Sensitivity to Barbiturates and Brain Gamma-Aminobutyric Acid

Abstract

The correlation between alteration in brain sensitivity to barbiturates and changes in brain gamma-aminobutyric acid levels was investigated. The following conditions were utilized to alter the brain sensitivity of mice or rats to barbiturates, 1) exposure to hypobaric hypoxia, 2) septal lesions, 3) treatment with desipramine, sodium nitrite or pargyline, 4) social deprivation, and 5) abrupt withdrawal following chronic barbiturate or ethanol administration. The first three of these conditions have been known to increase the brain sensitivity to barbiturates, while the last two conditions are known to decrease the sensitivity of brain neurons to barbiturates. The brain levels of gamma-aminobutyric acid were determined after the above treatments. Wherever necessary, the mechanism of alteration in gamma-aminobutyric acid was investigated by measuring activities of the enzymes, glutamic acid decarboxylase and gamma-aminobutyric acid transaminase. Acute Hypoxia Exposure of mice to hypobaric hypoxia (364 mm Hg , p02 = 76 mm Hg ) for 30 or 60 minutes at 22 or 30°C ambient temperature, produced elevation in brain level s of gamma aminobutyric acid. Only hypoxia was found to affect brain gamma-aminobutyric acid. Ambient temperature or duration of hypoxia exposure did not affect or interact with the effect of hypoxia on brain gamma-aminobutyric acid. These data suggest that hypoxia induced-elevation in brain gamma-aminobutyric acid may lower the threshold of brain neurons to drug induced depression. Septal Lesions Bilateral lesions of the septal area markedly potentiated narcosis due to barbital suggesting that alteration in neuronal excitability had taken place. There was no difference in the levels of brain gamma-aminobutyric acid between the septal rats and sham-operated or normal control rats. Therefore, the effect of septal lesions on the brain sensitivity does not appear to be related to alteration in brain gamma-aminobutyric acid. Drug Treatments Desipramine, ambient temperature and their interaction had a significant effect on brain gamma-aminobutyric acid. At 22°C, desipramine produced hypothermia and elevated brain gamma-aminobutyric acid levels. At 30°C ambient temperature desipramine ceased to reduce body ternperature and brain gamma-aminobutyric acid. In mice treated with desipramine at the lower ambient temperature, there was a dose-response relationship between the amount of drug administered and the elevation in brain gamma-aminoii butyric acid. Hypothermia due to desipramine appears to be important in the elevation of brain gamma-aminobutyric acid. These findings suggest that reduced brain excitability due to high gamma-aminobutyric acid may alter the response of brain neurons to barbiturates. At 22°C, sodium nitrite produced hypothermia and