Publication Date

2009

Document Type

Thesis

Committee Members

David Cool (Committee Member), James Lucot (Advisor), Courtney Sulentic (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Sarin (GB) is a toxic organophosphate (OP) nerve agent that was released in the Gulf War and was used in terrorist attacks in Japan. People who survive such attacks exhibit various long-term effects including alterations in neuropsychological performances. It has also been hypothesized that the Gulf War Illness could be a result of low level exposure to OP's. In order to understand the effect of low dose exposure to GB on physiological and behavioral functions, we analyzed the levels of monoamines and their metabolites in different brain areas after exposure of mice to a sublethal dose of GB. Mice (male C57BL/6) were injected subcutaneously once a day for 2 days, with 0.05 LD50 or 0.4 LD50 of GB followed by behavioral testing in the open field environment, elevated plus maze and for fear potentiated startle. The mice did not show signs of cholinergic toxicity. They were sacrificed at 1, 4 and 8 weeks with collection of brains for neurochemical analysis. In both dose groups and time points, a significant decrease in the usage of dopamine (DA) was observed in the frontal cortex (FC) region of the brain which may account for a number of symptoms of the Gulf War veterans. There was an increase in the usage of DA in the amygdala at 4 weeks but not at 1, 8 weeks, indicating a reversible effect. No significant change observed in the DA activity of the caudate nucleus which was consistent with no change in the motor activity in the open field studies. In addition to this, the levels of serotonin (5HT) were transiently elevated in all the brain regions studied. The FC is innervated mainly by the A10 group of dopaminergic cell bodies located in the ventral tegmental area (VTA) of the brain. The amygdala, in addition to A10, also receives projections from the A8 group of dopaminergic cell bodies in the retrorubral nucleus (RRN) - accounting for the difference from the FC. The caudate nucleus is innervated mainly by the A9 group of dopaminergic cell bodies located in the substantia nigra (SN) region of the brain. Data strongly suggests that even low dose of sarin has potent long-term, region specific effects on other neurotransmitter systems. Further experiments are necessary to evaluate the relationship between these modifications and the neuropsychological disorders reported after asymptomatic exposure to OPs.

Page Count

71

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2009

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