CLONIDINE PROTECTION FROM THE TOXICITY OF SOMAN, AN ORGANOPHOSHPATE ACETYLCHOLINESTERASE INHIBITOR, IN THE MOUSE

Abstract

Mice pretreated with the centrally active alpha-2 adrenergic agonist, clonidine, were protected from several of the toxic manifestations of soman, an organophosphate acetylcholinesterase inhibitor. The protection resulted in increased survival rates and a reduction in centrally mediated symptoms of soman, including tremor and straub tail, as well as one peripheral muscarinic symptom, excessive salivation. Doses of clonidine between 0.1 and 1 mg/kg, administered between 5 and 40 min before LD80 to LD90 doses of soman, produced significant protection. Pretreatment with atropine (25 mg/kg) also protected against soman toxicity. When atropine was combined with clonidine, the degree of protection afforded by the combination was greater than that predicted for a simple additive effect. Mice protected by atropine from the initial toxicity of soman frequently died within 24 h; no such delayed lethality was observed with protective doses of clonidine. Clonidine noncompetitively inhibited acetylcholinesterase activity in vitro and after in vivo administration at protective doses. At brain concentrations obtained after in vivo administration in protective doses, clonidine also inhibited ligand binding to cortical muscarinic receptors in vitro. The protective effects of clonidine are likely to involve multiple effects, including blockade of acetylcholine release and postsynaptic muscarinic receptors and transient inhibition of acetylcholinesterase.