Anticonvulsant effects of diazepam and MK-801 in soman poisoning

Abstract

An animal model was developed to evaluate the anticonvulsant effects of diazepam and MK-801 in soman poisoning and to examine the possible mechanism of soman-induced convulsions. The oxime HI-6 (125 mg/kg,i.p.) was given to male rats, to increase survival, 30 min prior to 180 μg/kg, s.c. (equivalent to 1.6 × LD 50) of soman, which produced 100% occurrence of convulsions. Initially, diazepam was studied with or without the concomitant administration of various doses of atropine sulfate 30 min prior to soman challenge. Diazepam (1.25–10.0 mg/kg, i.m.) alone did not prevent soman-induced convulsions. In the presence of 2, 4, 8, and 16 mg/kg of atropine, the anticonvulsant ED 50 doses of diazepam were 0.490, 0.257, 0.132 and 0.136 mg/kg, respectively. Atropine sulfate at a dose of 16 mg/kg prevented the soman-induced hypersecretion, showed some anticonvulsant activity and provided a good motor recovery. MK-801 by itself, at or above 1 mg/kg, prevented convulsions, but markedly potentiated the lethal effects produced by soman. With atropine (16 mg/kg), the anticonvulsant ED 50 for MK-801 was 0.037 mg/kg, which indicated that MK-801 was about 4 times as potent as diazepam, and the lethal interactions between MK-801 and soman were suppressed. The findings indicate that, in soman poisoning, diazepam and MK-801 are effective anticonvulsants in the presence of the anticholinergic atropine sulfate. The possible sequence of events and neuropharmacological mechanism of soman-induced convulsions are discussed.