Lack of Reproducibility of Gulf War Illness-like Behavioral Effects in War-related Chemical Agents and Stressor Exposure Rat Models

Gulf War illness (GWI) is characterized by a range of neurological and neuropsychiatric symptoms, including chronic pain, fatigue, mood problems, and cognitive issues. The pathophysiology is associated with war-related environmental chemical exposure and psychological stress, which are known to disrupt glutamatergic synaptic structure and function. The goal of this study was to evaluate the efficacy of the investigational new drug LH-001, a candidate for enhancing tripartite glutamatergic synapses, in a rat model of GWI. We began by attempting to induce GWI-like phenotypes in rats using a previously published protocol involving exposure to specific chemical agents and mild stress. However, these efforts were unsuccessful, as the expected GWI symptoms were not observed. We then performed two protocol modifications–using more potent chemical exposures and higher stress levels–but were still unable to produce the desired phenotypes. Our results highlight significant issues with the reliability of current GWI rat models. A comparative analysis of other studies suggests that GWI-like behavioral effects, when induced in rats by chemical agents and stress, show a broader lack of reproducibility across different laboratories. This calls into question the robustness of current rat models for GWI and poses challenges for preclinical drug development.