John J. DeFeo

Decreased potency of CNS depressants after prolonged social isolation in mice

SummaryThe duration of hypnosis induced by hexobarbital, pentobarbital, chloral hydrate or barbital was markedly reduced after prolonged social isolation of male mice. Hexobarbital and pentobarbital were affected more than chloral hydrate and barbital. The onset of barbital hypnosis was not affected. The in vitro metabolism of hexobarbital by hepatic microsomal enzymes was enhanced in isolated mice with an overall increase in liver weight. Mice deprived of social interaction gained righting reflex at a higher body level of hexobarbital as compared to the undeprived animals. These data show that chronic deprivation of social stimuli in mice increased the drug-metabolizing activity of hepatic microsomes and raised arousal levels such that CNS susceptibility to drugs was altered.

Liver enlargement and modification of hepatic microsomal drug metabolism in rats by pyrethrum

Abstract Oral administration of pyrethrum to male rats at 200 mg/kg for 23 days resulted in liver enlargement with decreases in hepatic DNA concentrations. While total lipid concentrations were increased significantly, the increases did not account for the enlargement. Protein concentrations of whole liver homogenates, 9000 g supernatants and the 105,000 g pellet were not different from controls. No significant changes occurred in hepatic water concentrations. Significant decreases in hexobarbital-induced hypnosis without concomitant changes in barbital-induced hypnosis suggested a pyrethrum-caused alteration in hepatic drug metabolism. The activities of hepatic microsomal enzymes responsible for EPN detoxification, p -nitroanisole demethylation and hexobarbital oxidation were increased to 150, 173 and 241% of control, respectively. No significant increases were noted in the demethylation of aminopyrine or oxidation of l -tryptophan. Increases in liver weight, the detoxification of EPN and demethylation of p -nitroanisole were found to be dose-related. Small increases in enzyme activities were observed at the lowest dose used of 85 mg/kg/day for 15 days. At a daily dose of 500 mg/kg/day, liver weights and enzyme activities were increased up to 17 days of treatment but returned to control level within 7 days after cessation of treatment. NADPH cytochrome c reductase activity and P-450 concentration were also increased. At high dose levels, pyrethrum will cause induction of microsomal enzymes.

Alterations in brain sensitivity and barbiturate metabolism unrelated to aggression in socially deprived mice

Male and female mice deprived of social interactions showed increased resistance to hexobarbital narcosis. However, only the isolated males developed aggressiveness. The more rapid disappearance of hexobarbital from the whole body of isolated mice and the higher drug concentration at awakening in these animals indicate enhanced hepatic degradation with a concomitant increase in CNS excitability. Development of aggressiveness in isolated male mice did not correlate temporally with the reduced response to hexobarbital. These data suggest that alterations in barbiturate sensitivity and development of aggressiveness following social deprivation have different biological bases.

Effect of acute hypoxia on brain-sensitivity and metabolism of barbiturates in mice

SummaryAcute exposure of mice to hypobaric hypoxia, or reduced oxygen at normal pressure, markedly potentiated barbiturate-induced hypnosis. The mice showed lower body concentration of pentobarbital on awakening and reduced rate of pentobarbital disappearance from the body during exposure to the hypoxic environment. These data suggest that acute exposure to hypoxia depresses in vivo metabolism of pentobarbital and enhances CNS sensitivity to the barbiturates.

Protection against m-fluorotyrosine convulsions and lethality in mice exposed to hypobaric hypoxia

reduction of the contractions induced in the stomach preparation. This supports the results of one further separate experiment on longitudinal stomach strips where imolamine (10 pg/ml) did not alter the acetylcholine dose-response curve but butalamine (10 ,ug/ml) caused a shift to the right and a flattening of the curve. From these preliminary experiments, it would appear that butalamine is a more effective smooth muscle relaxant compound than imolamine. It has a similar potency to aminophylline on isolated human smooth muscle. Imolamine has a variable action on tone, producing an increase in ileum and uterus and a decrease in stomach. We thank our surgical colleagues for providing us with the operation specimens used in this study. The work has been supported by a grant from the Board of Governors of St. Bartholomews Hospital. Butalamine and imolamine were supplied by Rona Laboratories Ltd.

Characterization of the exudate induced by the antibiotics muconomycin A and muconomycin B

Abstract Seven daily intraperitoneal doses (0.25 mg/kg) of the antibiotics muconomycin A (M-A) or muconomycin B (M-B) induced large volumes (10–20 ml) of peritoneal inflammatory exudate in rats. This exudate had the same general electrolyte and protein composition as has been reported for other mammalian edema fluids. In both antibiotic-treated groups the exudate contained lower concentrations of sodium, albumin, and globulin, and greater amounts of potassium, calcium, and phosphorus, than did blood serum. M-B-treated rats had lower chloride levels in exudate than in serum. Both antibiotics cause polymorphonuclear neutrophilia and lymphopenia, conditions characteristic of an inflammatory state in the rat. Both antibiotics appear to be among the most potent nonnitrogenous compounds known to induce inflammation.

Differential Effect of Hypobaric Hypoxia on Potency of GNS Depressants in Rats and Mice

Summary Acute exposure of mice and rats to hypobaric hypoxia (364 mm Hg, 10% O2) enhanced the depressant effects of sodium barbital, sodium pentobarbital, and chloral hydrate. Mice were far more sensitive than rats, barbital hypnosis being affected to the greatest extent. In addition, hypothermia observed under the hypobaric environment was greater in mice than in rats. This investigation was supported by PHS Training Grant No. 1T01ES 00104 from the Division of Environmental Health Sciences.