Hypnotic activity, distribution and metabolism of barbital in stressed-barbital tolerant rats

Chronic environmental stress has been reported in animals to cause altered drug activity, duration of action and toxicity. The purpose of the present investigation was to determine the extent to which the barbital activity is altered by long term environmental stress, and the possible mechanism which produces this altered activity. Albino rats were stressed by partial restriction of movement. Restriction cages of mesh wire were employed for this purpose and the temperature in the room was maintained at 24° C. ± 2° C. The following parameters were studied in the present study. The induction time and duration of hypnosis were determined at different dosage levels of barbital, 2 hours as well as 26 hours after the animals were removed from the stress situation. Induction time and duration of hypnosis were also observed after chronic pre-treatment with barbital. The experimental agent, [beta]-diethylaminoethyl diphenylpropylacetate hydrochloride (SKF-525A) was also injected in selected groups to determine its effect on the activity of barbital sodium in non-stressed animals and in animals stressed by restriction of movement. In order to study the distribution and metabolism of barbital, radioactive barbital was employed. Body organs such as plasma, liver, kidney and brain were collected after the animals were sacrificed at 40, 120 minutes and at the time of regaining the righting reflex after injection of barbital-2-C-14. The Packard liquid scintillation counter was used for isotope counting. For the metabolism study, paper chromatography and liquid scintillation techniques were used. The urinary excretion of barbital-2-C-14 was also determined at several intervals. In order to elucidate the mechanism by which barbital response is altered in stressed rats, measurement of corticosterone levels in plasma in selected groups of rats was conducted. The following observations vzere made: 1. Tolerance to barbital sodium was demonstrated in all dosage levels studied (300 mg/kg; 250 mg/kg; and 200 mg/kg) in stressed animals after the second dose. 2. SKF-525A ([beta]-diethylaminoethyl diphenylpropylacetate hydrochloride) prolonged the sleeping time in stressed and nonstressed rats. 3. Long term pre-treatment of rats with barbital sodium (100 mg/kg for 6 and 12 days) caused an appreciable tolerance to a challenging 7 dose C3G0 mg/kg) and the tolerance disappeared after four days of rest in both cases. 4. The percent of urinary metabolites of barbital in stressed animals was greater than in control rats. There was no difference in percent of barbital metabolites in SKF-525A pre-treated and non-pre-treated rats. 5. Maximum radioactivity was found in kidney, liver and plasma of the organs and tissues studied. 6. Maximum radioactivity 120 minutes after injection was found in liver, kidney and plasma; and after 40 minutes in liver. 7. An appreciably low level of radioactivity was found in the brains of SKF-525A pre-treated rats, compared to non-pre-treated rats. 8. No significant difference was observed in liver weights (percent of body weight) between stressed and non-stressed animals. The differences between mean adrenal gland weights were also no significant. In rats pretreated with SKF-525A, the liver weights were observed to be low. The adrenal glands were found to be heavier in SKF-525A pre-treated rats, than in non-pre-treated rats. 9. Plasma corticosterone was found to be elevated at 40 minutes after injection of barbital sodium and at time of regaining of righting reflex in stressed and non-stressed rats.Pharmacy, College o