title: In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate.
abstract: Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure.
authors.affiliation: Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: O'Donnell
authors.forename: John H
authors.initials: JH
authors.lastname: McDonough
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Shih
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004569:Electroencephalography; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D017551:Microdialysis; D015999:Multivariate Analysis; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D012524:Sarin / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D000109:Acetylcholine; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D018698:Glutamic Acid; D009946:Organothiophosphorus Compounds; D012524:Sarin; C009680:VX-agent