Date of Award

1976

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Harbans Lal

Abstract

Rats were exposed to continuous inhalation of ethanol vapors in an inhalation chamber plus daily injections of an alcohol dehydrogenase inhibitor pyrazole (68 mg/kg, i.p.). Ethanol vapors entered the inhalation chamber at flow rates of from o.45 liters/min. to 0.95 liters/min. which when mixed with a constant stream of air (5.0 liters/min) produced chamber concentrations of from approximately 8.8 mg/liter to 26.5 mg/liter. Rats exposed to these conditions for 5 to 7 days developed blood ethanol levels of 0.83± 0.09 mg/ml/blood to 2.19 ± 0.14 mg/ml/blood. Administration of pyrazole with or without ethanol caused weight loss in these rats. Rats developed tolerance to ethanol after continuous inhalation of ethanol vapors for 5 days demonstrated by increased onset and decreased duration of ethanol- induced narcosis. After 5 days of continuous ethanol inhalation rats became physically dependent on ethanol and developed withdrawal signs of piloerection, abnormal posture, tremors, convulsions, headshakes, tail-lifts and mortality upon cessation of ethanol administration. The four withdrawal signs of piloerection, abnormal posture, tremors and convulsions were combined into an ethanol withdrawal syndrome measurement. Pretreatment of ethanol dependent rats 30 minutes prior to 36 hours of ethanol withdrawal, the period of maximum intensity of the withdrawal syndrome, with ethanol (2.0 g/kg, orally), chlordiazepoxide (40 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) significantly reduced the intensity of the ethanol withdrawal syndrome as measured during the thirty-sixth hour of ethanol withdrawal. Rats withdrawn after continuous inhalation of ethanol vapors showed intense aggression (attacks and bites, rearing and vocalizations) after small doses of apomorphine (2 . 5 mg/kg, i.p.) or ct-amphetamine (2.0 mg/kg, i.p.), although little spontaneous aggression was seen. Other ethanol withdrawal signs returned to near control levels by 72 hours after ethanol withdrawal, however drug-induced aggression was present for at least 7 days after ethanol withdrawal. Administration of ethanol (4.0 g/kg, orally), chlordiazepoxide (80 mg/kg, i.p.) or morphine (10 mg/kg, i.p.) 30 minutes prior to apomorphine administration (2.5 mg/kg, i.p.) significantly reduced apomorphine-induced aggression in ethanol withdrawn rats. During withdrawal from ethanol, mortality was 20% among rats exposed for 5 days to ethanol inhalation and not treated with any drugs during' withdrawal. None of the drugs used in this study significantly reduced the mortality rate in ethanol withdrawn rats . However, administration of chlordiazepoxide (160 mg/kg, i.p.) prior to the thirty-sixth hour of ethanol withdrawal resulted in a significant increase in the mortality to 75%. This same dose of chlordiazepoxide administered intraperitoneally to untreated rats resulted in a mortality of 66.7% of the rats treated within 36 hours after injection.

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