Effects of chronic and acute stress on barbital activity in the rat



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Chronic environmental stress has been reported to cause altered drug activity. The purpose of this investigation was (a) to examine the effect of chronic stress upon barbital activity; (b) to find possible clues to the mechanism of barbital tolerance; and (c) to study the effects of acute-chronic stress programs on barbital activity. Male or female albino rats were stressed for fourteen days by partial restriction of movement in an environment maintained at 22° ± 2° C., relative humidity 30 ± 2 per cent. Control rats were maintained under conditions which were relatively free from environmental stress. The effects of the above two treatments on induction time, and duration of action of barbital sodium (100 mg/kg., I.P.; 150 mg./kg., I.P; 200 mg./kg., I,P., or S.C.) and pentobarbital sodium (35 mg./kg., I.P) were studied. The drug was injected 2 hours (Dose I), 26 hours (Dose II), 50 hours (Dose III), and 74 hours (Dose IV) after removal from the 'stress' or the 'stress-free' environment. Barbital sodium (300 mg./kg., S.C.) and pentobarbital (35 mg-/kg., S.C.) was administered 2 hours, 26 hours, and 146 hours (Dose III) after removal from the 'stress' or the 'stress-free' environment. In all of the above groups of animals, hind-leg ligation stress was applied for 2.5 hours, one hour prior to Dose III. In order to investigate the barbital hypersensitivity, chronically stressed rats were given Doses I and II (200 mg/kg. as above) and then maintained 'stress-free' for 18 days. Doses III and IV were then given. After a second 18 day period barbital sodium, hexobarbital sodium, and ether anesthesia were studied. Under the conditions of the present experiment, longterm environmental stress patterns were shown to have the following effects: 1. Restriction of movement for 14 days increased induction time and decreased sleeping time after Dose I and decreased sleeping time of the males in Dose II (200 mg/kg., I.f.), as compared to controls. 2. By subcutaneous injection of 200 mg./kg. of barbital sodium, sleeping time was decreased in Dose II of stressed rats as well as controls. Decrease of sleeping time from Dose II, compared with Dose I, was 19.3 per cent in stressed rats, 42.6 per cent in controls. However, by administration of 300 mg./kg., S.C., sleeping time was decreased in Dose II of only stressed males and females. 3. After acute stress, hypersensitivity was demonstrated in Dose III as follows: (a) 100 mg./kg., I.P., pre-stressed males and females and control females; (b) 150 mg./kg., I.P., pre-stressed males and females; (c) 200 mg./kg., I.P., pre-stressed males and females; (d) 200 mg./kg., S.C., pre-stressed and controls; 4. Hypersensitivity was demonstrated in stressed rats even 5 days after Dose II (300 mg./kg., barbital sodium, S.C.). 5. No hypersensitivity was produced with Dose III by pentobarbital sodium (35 mg/kg., I.P.). Sleeping time of Dose IV was increased in the males and decreased in females compared with Dose III in pre-stressed rats. 6. Administration of sedative dosage levels of barbital in Dose I (100 and 150 mg./kg., I.P.) produced tolerance in response to Dose II (hypnotic dose, 200 mg-/kg.), in pre-stressed as well as non-prestressed rats in both sexes compared to previous experiment, where Dose I was 200 mg/kg. 7. Chronically stressed rats were given Dose I and Dose II (200 mg./kg., barbital sodium, I,P.), then maintained 'stress-free' for 18 days. Dose III and IV were then given. Significantly decreased induction time and increased sleeping time were recorded after Dose III in pre-stressed rats as well as non-prestressed rats in both sexes. There was tolerance in pre-stressed, rats in Dose IV (compared with Dose III). After a second interval of 18 days, hypersensitivity was reproduced in same manner with Dose V in stressed and non-stressed rats; however, there was no sleeping time difference between Dose V and VI in hexobarbital or barbital anesthesia. Stressed rats showed decreased response to ether after the second interval of 18 days. 8. During 14 days of restriction of movement, the increase of body weight of males and females was about one half that of controls.