Changes in extracellular striatal acetylcholine and brain seizure activity following acute exposure to nerve agents in freely moving guinea pigs.
Organophosphorus nerve agents irreversibly inhibit acetylcholinesterase (AChE) in the peripheral and central nervous systems, causing an increase in the concentration of acetylcholine (ACh) in the synapse or neuromuscular junction and subsequent adverse effects. In this study, in vivo microdialysis was utilized to collect samples from the striatum for monitoring changes in extracellular ACh levels along with cortical electroencephalographic (EEG) recordings for identifying seizure activity after acute subcutaneous (s.c.) exposure to 1.0 x LD(50) of the nerve agents sarin, soman, or one of two V-type agents (VX, or a Russian V-agent, designated VR) in unanesthetized freely moving guinea pigs. Based on EEG recordings, these animals were subsequently divided into groups that developed seizures (S) and those that did not develop seizures (NS). Maximum ACh levels in the striatum were observed at 60-70 min for sarin and soman S groups and 105 min for VX and VR S groups. In all NS groups the greatest increase in extracellular ACh occurred within 30 min after exposure, although in the sarin NS group a few sporadic increases of ACh from control occurred. Animals that developed seizures, regardless of the nerve agent, had significantly higher extracellular striatal ACh levels compared to the controls or those animals that did not develop seizures, yet both S and NS groups displayed similar levels of blood AChE inhibition. Regardless of the agent, all animals in the non-seizure groups survived 24 h, while lethality (25-42%) was observed only in animals that experienced seizure activity.
O'Donnell
John C
JC
Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
McDonough
John H
JH
Shih
Tsung-Ming
TM
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004569:Electroencephalography; D006168:Guinea Pigs; D008297:Male; D009946:Organothiophosphorus Compounds / Q000633:toxicity; D012524:Sarin / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D012999:Soman / Q000633:toxicity
D000109:Acetylcholine; D002619:Chemical Warfare Agents; D002794:Choline; D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D012524:Sarin; D012999:Soman; C009680:VX-agent; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate