Comparison of extracellular striatal acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs

Abstract

Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 × LD₅₀ subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure.

Keywords::

• Acetylcholine
• acetylcholinesterase
• cholinesterase inhibitors
• cyclosarin
• in vivo microdialysis
• lethality
• nerve agents
• organophosphorus compounds
• seizure activity
• tabun.

Acknowledgements

The authors express their appreciation for the excellent technical assistance of Jeffrey Koenig.

The opinions or assertions contained herein are the private views of the authors, and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.

Declaration of interest

This research was supported by the Defense Threat Reduction Agency-Joint Service and Technology Office, Medical Science and Technology Division. The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.