Date of Award


Document Type

Open Access Dissertation




College of Arts and Sciences

First Advisor

Sandra Kelly


Upon returning from the first Gulf War, soldiers cited a plethora of unexplained physical and cognitive deficits which have since been termed Gulf War Illness (GWI). Presentation of GWI is positively correlated with pyridostigmine bromide (PB) use, which was prophylactically administered to soldiers in response to threats of chemical warfare. To test the overarching hypothesis that PB interacted with stress of deployment to alter neural, endocrine, and immune systems, the following studies used a 2×2 rodent model with 14 days of drug treatment (vehicle; PB) and 10 days of repeated restraint stress (stressed) or non-stressed-control conditions. Results indicate that PB decreases cholinesterase activity acutely but sensitizes it by three months post-treatment selectively in rats also subjected to stress. Similarly, only rats in the PB-stressed condition exhibit elevations in corticosterone three months post-treatment. These results suggest that PB and stress interact to progressively disrupt homeostasis in peripheral measures. To test whether PB and stress also interact to influence central neurotransmitter function, an in vivo microdialysis study was performed in a separate GWI cohort where rats were subjected to an immune challenge (30 μg/kg lipopolysaccharide; LPS) followed 48 hours later by an acute restraint stress challenge. Acetylcholine and glutamate levels were assessed in both the prefrontal cortex (PFC) and hippocampus. Results indicate that a history of restraint stress attenuates the cholinergic and glutamatergic responses to both LPS and restraint stress challenges. PB in the absence of stress decreases the cholinergic response to restraint stress challenge in both the PFC and hippocampus. In contrast, PB in combination with a history of restraint stress interact to preferentially increase the glutamatergic response in the hippocampus. These results indicate that PB preferentially disrupts cholinergic systems whereas PB and stress interact synergistically to disrupt glutamatergic systems, providing insight into possible mechanisms underlying cognitive impairments observed in soldiers with GWI.