Anticholinergics,
benzodiazepines and
N-methyl-D-aspartate (
NMDA) antagonists have been shown to modulate the expression of
nerve agent-induced
seizures. This study examined whether the
anticonvulsant actions of these drugs varied depending on the duration of prior seizure activity. Rats implanted with
electrodes to record electroencephalographic (EEG) activity were pretreated with the
oxime HI-6 (125 mg/kg, IP) to prolong survival, and then challenged with a
convulsant dose of the
nerve agent soman (180 micrograms/kg, SC); treatment compounds (
scopolamine,
diazepam,
MK-801,
atropine,
benactyzine, and
trihexyphenidyl) were delivered 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 remained the same.
Diazepam, and especially
MK-801, enhanced the lethal actions of
soman by potentiating the respiratory depressant effects of the agent;
scopolamine given prior to
diazepam or
MK-801 protected against 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 eventual loss of
anticonvulsant activity if the seizure had progressed for 40 min. In contrast,
benactyzine and
trihexyphenidyl showed a third profile of activity: There was a smaller increase in
drug dosage required for
anticonvulsant activity as seizure duration increased, and both drugs could terminate
seizures that had progressed for 40 min. The early
anticonvulsant action of
anticholinergics is interpreted as a specific effect that blocks the primary
cholinergic excitatory drive that initiates, and first maintains,
nerve agent seizures. If allowed to progress, the seizure activity itself recruits excitatory
neurotransmitter systems (i.e.,
NMDA) that eventually maintain the seizure independent of the initial
cholinergic drive. This is indicated by the eventual ineffectiveness of
scopolamine and
atropine as the duration of the seizure progresses.
Diazepam and
MK-801 appear to act to moderate
nerve agent seizures by enhancing inhibitory activity (
diazepam) or dampening the secondarily activated noncholinergic excitatory system (MK-801).
Benactyzine and
trihexyphenidyl represent compounds that possibly have both
anticholinergic and
NMDA antagonistic properties.