Nicotinic mechanisms contribute to soman-induced symptoms and lethality.
The symptoms and lethality of intoxication with the acetylcholinesterase inactivator soman are attributed primarily to excessive activation of muscarinic acetylcholine receptors; nicotinic activation is considered of less importance, a notion that may rely on studies that have used nicotinic antagonists at low doses. In this study pretreatment with the centrally acting nicotinic antagonist mecamylamine, 20mg/kg, but not 2mg/kg, prolonged survival in mice exposed to soman, 250 microg/kg (1.5 LD(50)), from 14+/-3 to 135+/-38 min (mean+/-S.E.M.; surviving animals were killed 240 min after soman administration). Pretreatment with the muscarinic blocker scopolamine, 2 or 20mg/kg (but not 0.5mg/kg) prolonged survival significantly (mean for both groups: 91 min), but the animals responded to soman with immobility, irregular respiration, fasciculation, and short episodes of convulsive crawling. These symptoms were absent in animals pretreated with scopolamine plus mecamylamine, both drugs 20mg/kg, a suggestion that they were caused by activation of nicotinic receptors. All animals pretreated with scopolamine and mecamylamine (both drugs 20 mg/kg) survived the full 240 min observation period. Administration of mecamylamine, 5 mg/kg, 5 min after soman exposure to scopolamine-pretreated animals reduced fasciculation and respiratory irregularity and prolonged survival compared to scopolamine alone, but mecamylamine, 20 mg/kg, given 10 min after soman exposure shortened survival (18+/-1 min). These results suggest that nicotinic activation plays an important part in soman-induced symptomatology and lethality but also that nicotinic antagonists given in large doses after soman exposure may have untoward effects.
Hassel
Bjørnar
B
Norwegian Defence Research Establishment, P.O. Box 25, N-2027 Kjeller, Norway. bjornar.hassel@ffi.no
D000110:Acetylcholinesterase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced / Q000517:prevention & control; D007928:Lethal Dose 50; D008464:Mecamylamine / Q000008:administration & dosage; D051379:Mice; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D009127:Muscle Rigidity / Q000139:chemically induced / Q000517:prevention & control; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000008:administration & dosage; D011041:Poisoning / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D012601:Scopolamine / Q000008:administration & dosage; D012999:Soman / Q000633:toxicity*; D013997:Time Factors; D014202:Tremor / Q000139:chemically induced / Q000517:prevention & control
D002619:Chemical Warfare Agents; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D008464:Mecamylamine; D009538:Nicotine; D012999:Soman; D012601:Scopolamine; D000110:Acetylcholinesterase