Single whole-body exposure to sarin vapor in rats: long-term neuronal and behavioral deficits.
Freely moving rats were exposed to sarin vapor (34.2+/-0.8 microg/l) for 10 min. Mortality at 24 h was 35% and toxic sings in the surviving rats ranged from sever (prolonged convulsions) through moderate to almost no overt signs. Some of the surviving rats developed delayed, intermittent convulsions. All rats were evaluated for long-term functional deficits in comparison to air-exposed control rats. Histological analysis revealed typical cell loss at 1 week post inhalation exposure. Neuronal inflammation was demonstrated by a 20-fold increase in prostaglandin (PGE(2)) levels 24 h following exposure that markedly decreased 6 days later. An additional, delayed increase in PGE(2) was detected at 1 month and continued to increase for up to 6 months post exposure. Glial activation following neural damage was demonstrated by an elevated level of peripheral benzodiazepine receptors (PBR) seen in the brain 4 and 6 months after exposure. At the same time muscarinic receptors were unaffected. Six weeks, four and six months post exposure behavioral evaluations were performed. In the open field, sarin-exposed rats showed a significant increase in overall activity with no habituation over days. In a working memory paradigm in the water maze, these same rats showed impaired working and reference memory processes with no recovery. Our data suggest long lasting impairment of brain functions in surviving rats following a single sarin exposure. Animals that seem to fully recover from the exposure, and even animals that initially show no toxicity signs, developed some adverse neural changes with time.
Grauer
Ettie
E
Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona, Israel. ettieg@iibr.gov.il
Chapman
Shira
S
Rabinovitz
Ishai
I
Raveh
Lily
L
Weissman
Ben-Avi
BA
Kadar
Tamar
T
Allon
Nahum
N
D000280:Administration, Inhalation; D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D003071:Cognition / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D005740:Gases; D007928:Lethal Dose 50; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D009474:Neurons / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000473:pathology* / Q000523:psychology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012524:Sarin / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D005740:Gases; D011963:Receptors, GABA-A; D011976:Receptors, Muscarinic; D012524:Sarin; D015232:Dinoprostone