caa a22 4500 445853271 CHVBK 20180317145420.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00204-011-0724-z doi (NATIONALLICENCE)springer-10.1007/s00204-011-0724-z In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate [Elektronische Daten] [John O'Donnell, John McDonough, Tsung-Ming Shih] 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. Springer-Verlag (outside the USA), 2011 Acetylcholine nationallicence Acetylcholinesterase nationallicence Choline nationallicence Electroencephalogram nationallicence γ-Aminobutylic acid (GABA) nationallicence Glutamate nationallicence Guinea pig nationallicence In vivo microdialysis nationallicence Nerve agents nationallicence Organophosphorus compounds nationallicence Sarin nationallicence Seizure activity nationallicence VX nationallicence ACh : Acetylcholine nationallicence AChE : Acetylcholinesterase nationallicence AMN : Atropine methyl nitrate nationallicence Asp : Aspartic acid nationallicence aspartate nationallicence ChE : Cholinesterase nationallicence CNS : Central nervous system nationallicence EAA : Excitatory amino acid nationallicence EC : Electrochemical nationallicence ED50 : Median effective dose nationallicence EEG : Electroencephalographic nationallicence Glu : Glutamic acid nationallicence glutamate nationallicence GABA : γ-aminobutyric acid nationallicence GB : Sarin nationallicence isopropyl methylphosphonofluoridate nationallicence GD : Soman nationallicence pinacolyl methylphosphonofluoridate nationallicence HPLC : High-pressure liquid chromatography nationallicence im : Intramuscular nationallicence LD50 : Median lethal dose nationallicence NS : No seizure nationallicence NT : Neurotransmitter nationallicence OP : Organophosphorus compound nationallicence OPA : o-phthalaldehyde nationallicence PNS : Peripheral nervous system nationallicence S : Seizure nationallicence SAL : Saline nationallicence sc : Subcutaneous nationallicence VX : o-ethyl S-(2-(diisopropylamino)ethyl) methylphosphonothioate nationallicence O'Donnell John Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P (Dr. T.-M. Shih), 3100 Ricketts Point Road, 21010-5400, Aberdeen Proving Ground, MD, USA aut McDonough John Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P (Dr. T.-M. Shih), 3100 Ricketts Point Road, 21010-5400, Aberdeen Proving Ground, MD, USA aut Shih Tsung-Ming Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P (Dr. T.-M. Shih), 3100 Ricketts Point Road, 21010-5400, Aberdeen Proving Ground, MD, USA aut Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1607-1616 0340-5761 85:12<1607 2011 85 204 https://doi.org/10.1007/s00204-011-0724-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-011-0724-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- O'Donnell John Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P (Dr. T.-M. Shih), 3100 Ricketts Point Road, 21010-5400, Aberdeen Proving Ground, MD, USA aut NATIONALLICENCE 700 1- McDonough John Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P (Dr. T.-M. Shih), 3100 Ricketts Point Road, 21010-5400, Aberdeen Proving Ground, MD, USA aut NATIONALLICENCE 700 1- Shih Tsung-Ming Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, ATTN: MCMR-CDR-P (Dr. T.-M. Shih), 3100 Ricketts Point Road, 21010-5400, Aberdeen Proving Ground, MD, USA aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1607-1616 0340-5761 85:12<1607 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer