Date of Award

1970

Degree Type

Dissertation

Degree Name

Doctor of Pharmacy (PharmD)

Department

Pharmaceutical Sciences

First Advisor

John J. DeFeo

Abstract

The mechanisms by which hypoxia or social isolation interact with drug action were investigated by the use of several parameters including drug-induced narcosis, convulsions, change in body temperature and various biochemical parameters.

Acute Hypoxia

Hypobaric hypoxia (364 mm Hg, 10% O2) enhanced. the depressant effects of barbital, pentobarbital and chloral hydrate in mice and rats. Mice were far more sensitive than rats, barbital narcosis being affected to the greatest extent. Reduced oxygen (10%) at normal pressure also potentiated pentobarbital narcosis.

Hypothermia during hypoxia was greater in mice than in rats. Mice exposed to hypoxia at 30°C instead of 22°C ambient temperature did not exhibit hypothermia. Hypoxia at 22°C enhanced and prolonged the hypothermia induced by barbiturates and chloral hydrate. At 30°C hypoxia showed considerably less potentiation of barbital narcosis and hypothermia than at 22°C. These parameters were moderately reduced with chloral hydrate and unaffected with respect to pentobarbital.

Convulsions produced by intraperitoneal semicarbasize, m-fluorotyrosine or methionine sulphomimine were significantly reduced in mice exposed to hypoxia. Seizures due to intracerebral semicarbazide were also antagonized by hypoxia.

Hypoxic mice showed lower body concentration of pentobarbital on awakening and reduced rate of pentobarbital disappearance from the body than animals breathing room atmosphere.

Administration of sodium nitrate to mice markedly potentiated barbiturate narcosis. The hypothermia and methemoglobinemia produced by nitrite showed a temporal relationship to the potentiation of hexobarbital narcosis. Both reduction in body temperature and enhancement of barbital narcosis after sodium nitrite were prevented at 30°C ambient temperature, but potentiation of hexobarbital narcosis was unaffected.

Disappearance of hexobarbital from the whole-body of nitrite-treated mice was slower and barbiturate concentration at awakening was lower in these animals as compared to control mice.

Sodium nitrite did not inhibit hexobarbital metabolism in vitro or affect hexobarbital narcosis when injected intracerebrally.

Methylene blue effectively reduced nitrite-induced methemoglobinemia, but markedly potentiated barbiturate narcosis in the absence of nitrite.

Seizures produced by intracerebral semicarbazide were antagonized by sodium nitrite injection.

Brain and plasma levels of intraperitoneal barbital C14 were reduced after exposure to hypobaric hypoxia or injection of sodium nitrite when the labelled compound was given with a depressant dose (300 mg/kg) of unlabeled barbital. Excretion of barbital C14, as measured by brain and plasma levels 6h after intraperitoneal injection, was lower in mice subjected to barbiturate narcosis during hypobaric hypoxia. Exposure to hypoxia or injection of sodium nitrite did not affect penetration of intravenously administered barbital C14 into brain.

These data suggest that hypoxia due to low ambient oxygen or injection of sodium nitrite decreases absorption, metabolism and excretion of barbiturates and lowers the threshold of brain neurons to drug-induced depression.

Social Isolation

Narcosis due to hexobarbital, pentobarbital, chloral hydrate or barbital was markedly reduced in male mice after 5 weeks of social deprivation. Socially deprived female mice also showed a decreased response to hexobarbital narcosis. However, only isolated males developed aggressiveness.

The metabolism of hexobarbital both in vivo and in vitro was enhanced in isolated animals. Mice deprived of social interactions gained righting reflect at a higher body level of hexobarbital as compared to the underpriced animals.

Development of aggressiveness in isolated male mice did not correlate temporally with the reduced response to hexobarbital.

Gonadectomy, but not adrenalectomy effectively prevented reduction of barbiturate potency and development of aggressiveness in socially deprived male mice.

Latency to avoidance of paw shock was significantly lower in socially deprived male mice. In addition, the decrement in avoidance produced by chlorpromazine in grouped mice was less pronounced in the deprived 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 and physical stimuli was altered. In addition, the anabolic steroids appear to be involved in this response. These observations further suggest that alterations in barbituated sensitivity and development of aggressiveness after social deprivation may have a different biological basis.

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