Date of Award

1972

Degree Type

Thesis

Degree Name

Master of Science in Pharmacology and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Harbans Lal

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 raised brain levels of gamma-aminobutyric acid. At 30°C ambient temperature sodium nitrite ceased to affect body temperature and brain gamma-aminobutyric acid. Even though, hypothermia due to sodium nitrite seems to be important in elevation of gamma-aminobutyric acid, elevation of gamma-aminobutyric acid is the result of sodium nitrite's ability to produce hypoxia. Pargyline induced potentiation of narcosis due to barbital was greater at 22°C than at 30°C ambient temperature. This suggested that pargyline alters the neuronal sensitivity to barbiturates at both the ambient temperatures. Pargyline also produced hypothermia and elevated brain gamma-aminobutyric acid at both the ambient temperatures. There was a greater degree of reduction in body temperature and elevation in brain gamma-aminobutyric acid when mice were treated with pargyline at 22°C. In pargyline treated mice, at 22°C, there was a dose-response relationship between the amount of drug administered and the degree of elevation in brain gamma-aminobutyric acid. These observations indicate that pargyline induced hypothermia causes elevation in brain gamma-aminobutyric acid. Further the increased concentrations of brain gamma-aminobutyric acid may in turn lower the threshold of brain neurons to barbiturates. Social Deprivation Chronic deprivation of social stimuli lowered brain gamma-aminobutyric acid levels decreased the activity of the gamma-aminobutyric acid synthesizing enzyme, glutamic acid decarboxylase and reduced total protein content in the brain. The activity of the gamma-aminobutyric acid degrading enzyme, gamma-aminobutyric acid transaminase, remained unaltered. These data suggest that reduced concentrations of gamma-aminobutyric acid might have raised arousal levels of the deprived mice such that their central nervous system susceptibility to drugs was altered. Further induced levels of gamma-aminobutyric acid were true reflection of glutamic acid decarboxylase. Drug Withdrawal The fluid intake of mice was restricted to increasingly concentrated solutions of phenobarbital for four weeks. Abrupt withdrawal resulted in convulsive activity in response to an auditory stimulation. There was no alteration in brain levels of gamma-aminobutyric acid in any of the groups tested. These data suggest that brain gamma-aminobutyric acid was not involved in the alteration of neuronal sensitivity following barbiturate withdrawal. Intoxicating blood levels of ethanol were maintained, by stabilizing blood ethanol-levels with daily injections of pyrazole, for 96 hours in mice housed in an atmosphere of ethanol vapor. On removal from the ethanol, mice developed withdrawal signs. The signs were graded to indicate the time course and intensity of the withdrawal syndrome. Eight and twenty-four hours following ethanol withdrawal mice were tested with barbital. Both the groups showed marked reduction in narcosis due to barbital. These observations suggested that ethanol withdrawal heightened the threshold of brain neurons to drug induced depression. The brain levels o1' gamma-aminobutyric acid were found to be lowered following eight hours of ethanol withdrawal. This indicates that lower than normal brain gamma-aminobutyric acid may cause an increase in neuronal excitability, which is revealed upon administration of the barbiturate.

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