Effects of Low-level Inhalation Exposure to Cyclosarin on Learned Behaviors in Sprague-Dawley Rats

Abstract

Behavioral and biochemical effects of low-level whole-body inhalation exposure to the chemical warfare nerve agent cyclosarin (GF) were evaluated. Sprague-Dawley rats were first trained on a variable-interval, 56-s (VI56) schedule of food reinforcement. The VI56 schedule specifies that a single lever press, following an average interval of 56 s, produces food reinforcement (i.e., a single food pellet). Subjects were then exposed to GF vapor at concentrations of 1.6–5.2 mg/m³, or air control, for 60 min. Following exposures, performance on the VI56 and acquisition and maintenance of a radial-arm maze (RAM) spatial memory task were evaluated during 55 test sessions over approximately 11 wk. GF exposures produced miosis in all subjects and other mild clinical signs of toxicity at the highest concentration. Convulsions were not observed in any subjects. GF exposures produced concentration-dependent decreases in acetylcholinesterase and butyrylcholinesterase activity. Additionally, blood assays revealed concentration-dependent levels of regenerated GF, thus verifying systemic exposure. The largest concentration of GF disrupted performance on the VI56 task. The deficit, however, resolved by the third postexposure test session. All subjects acquired, and maintained, performance on the RAM task, and no significant differences were seen as a result of GF exposure. No delayed effects from exposures were observed. These results demonstrate that, in rats, inhalation exposure to GF at levels below those producing convulsions and other severe clinical signs of toxicity may produce performance deficits on learned behaviors, but the deficits appear to not be persistent.

Acknowledgements

The authors thank Robert J. Mioduszewski, PhD, David Burnett, Ashima Saxena, PhD, Bhupendra P. Doctor, PhD, Jacquelyn Scotto, and Jill Jarvis for assistance with the studies and the article.

The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense, (para 4-3, AR 360-5). Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. All procedures were reviewed and approved by the institutes' Animal Care and Use Committees, and performed in facilities accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.

Portions of this study were presented at the 24th Army Science Conference, 2004, Orlando, FL.