PHARMACOLOGICAL MODULATION OF SOMAN-INDUCED SEIZURES

Anticholinergics, benzodiazepines and N-methyl-D-aspartate (NMDA) anta gonists have been shown to modulate the expression of nerve agent-indu ced seizures. This study examined whether the anticonvulsant actions o f these drugs varied depending on the duration of prior seizure activi ty. Rats implanted with electrodes to record electroencephalographic ( EEG) activity were pretreated with the oxime HI-6 (125 mg/kg, IP) to p rolong survival, and then challenged with a convulsant dose of the ner ve agent soman (180 mug/kg, SC); treatment compounds (scopolamine, dia zepam, MK-801, atropine, benactyzine, and trihexyphenidyl) were delive red IV at specific times after seizure onset. Both diazepam and MK-801 displayed a similar profile of activity: At both short or long times after seizure initiation the anticonvulsant efficacy of each drug rema ined the same. Diazepam, and especially MK-801, enhanced the lethal ac tions of soman by potentiating the respiratory depressant effects of t he agent; scopolamine given prior to diazepam or MK-801 protected agai nst the respiratory depression. Scopolamine and atropine showed a dose - and time-dependent effectiveness; the longer the seizure progressed the higher the dose of drug required to terminate the seizure, with ev entual loss of anticonvulsant activity if the seizure had progressed f or 40 min. In contrast, benactyzine and trihexyphenidyl showed a third profile of activity: There was a smaller increase in drug dosage requ ired for anticonvulsant activity as seizure duration increased, and bo th drugs could terminate seizures that had progressed for 40 min. The early anticonvulsant action of anticholinergics is interpreted as a sp ecific effect that blocks the primary cholinergic excitatory drive tha t initiates, and first maintains, nerve agent seizures. If allowed to progress, the seizure activity itself recruits excitatory neurotransmi tter systems (i.e., NMDA) that eventually maintain the seizure indepen dent of the initial cholinergic drive. This is indicated by the eventu al ineffectiveness of scopolamine and atropine as the duration of the seizure progresses. Diazepam and MK-801 appear to act to moderate nerv e agent seizures by enhancing inhibitory activity (diazepam) or dampen ing the secondarily activated noncholinergic excitatory system (MK-801 ). Benactyzine and trihexyphenidyl represent compounds that possibly h ave both anticholinergic and NMDA antagonistic properties.