Pharmacological modulation of soman-induced seizures.
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.
Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
J H
JH
McDonough
T M
TM
Shih
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001285:Atropine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001535:Benactyzine / Q000494:pharmacology; D003975:Diazepam / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D012999:Soman / Q000633:toxicity*; D014282:Trihexyphenidyl / Q000494:pharmacology
D000927:Anticonvulsants; D001535:Benactyzine; D016291:Dizocilpine Maleate; D014282:Trihexyphenidyl; D001285:Atropine; D012999:Soman; D003975:Diazepam