The involvement of the NMDA receptor complex in the protective effect of anticholinergic drugs against soman poisoning

Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes i n neuronal networks. This study reports on investigations designed to asses s the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which act s at these receptors, and scopolamine, which does not, was determined on so man-induced alteration in rat brain functions. Administration of soman (1xL D(50)) to pyridostigmine pretreated rats produced seizure activity (measure d by EEG monitoring) in all animals tested. Estimation of [H-3]MK-801 bindi ng to brain membranes from intoxicated rats revealed a marked decrease in B max value 24 but not 2 hrs following soman administration. The specific nat ure of these effects of soman was demonstrated by the findings that [H-3]fl unitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, whe n used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In cont rast, only caramiphen abolished soman-induced modifications in NMDA/ion cha nnel characteristics. Caramiphen displaced [H-3]MK-801 bound to the NMDA/io n channel complex, possibly by interacting with the Zn2+ site whereas scopo lamine did not. Moreover, caramiphen, but not scopolamine, partially protec ted mice from NMDA-induced lethality. Thus, it is suggested that an importa nt component of the protective efficacy of caramiphen against organophospha te poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties. (C)1999 Intox Press, Inc.