Direct microinjection of soman or VX into the amygdala produces repetitive limbic convulsions and neuropathology.
Rats were injected in the amygdala and other forebrain sites with nmolar amounts of the highly toxic organophosphate 'nerve agent' compounds soman or VX (O-ethyl-S-(2-diisopropylaminoethyl)-methylphosphonothioate) in an attempt to determine the mechanism(s) responsible for the permanent brain pathology that has been observed following systemic intoxication with these agents. Injections were performed using a stereotaxically guided microsyringe in animals maintained under halothane/oxygen anesthesia or using chronically implanted cannulae in conscious animals. Bilateral microsyringe injections of up to 11.0 nmol soman into the amygdala failed to evoke abnormal behavior or brain pathology. When rats were pretreated with lithium chloride, or when carbachol was coadministered, soman injections evoked repetitive clonic convulsions and neuropathology. Unilateral injections of 3.4 nmol of VX into the amygdala elicited convulsions and brain damage in 67% of the animals tested. Atropine pretreatment (15.0 mg/kg, i.p.) prevented the development of convulsions and brain damage. Neuropathology was observed only in animals that developed repetitive convulsions; the piriform and entorhinal cortex, amygdala, hippocampus and thalamus were the brain structures most consistently damaged. With unilateral injections, the damage was more severe on the side ipsilateral to the injection. The behavioral topography of the convulsions and the neuroanatomical distribution and nature of the subsequent pathology closely resemble that observed with systemic administration of these compounds. The results indicate that the nerve agents are not directly neurotoxic, that peripherally induced hypoxia or anoxia are unlikely mechanisms of the neuropathology, and that the brain damage produced by these compounds is primarily seizure-mediated.
U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
J H
JH
McDonough
C G
CG
McLeod
M T
MT
Nipwoda
D000679:Amygdala / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003292:Convulsants; D008297:Male; D008845:Microinjections; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology*; D012999:Soman / Q000008:administration & dosage / Q000633:toxicity*
D003292:Convulsants; D009946:Organothiophosphorus Compounds; D012999:Soman; C009680:VX-agent