Muscarinic and Nicotinic Mechanisms of Seizures Induced by Cholinesterase Inhibitors: Observations on Diazepam and Midazolam as Antagonists
The gross behavioral and EEG seizure-inducing effects of various cholinesterase inhibitors (ChEI) were compared to the cholinergic agonists arecoline and nicotine, and the classic convulsants pentylenetetrazol and strychnine in unanesthetized rats. It was also our purpose to determine the possible anticonvulsant activity of potential antagonists. Femoral arterial and venous cannulae, EEG (epidural) and EKG (Lead II) electrodes were surgically implanted under halothane-oxygen anesthesia into adult Sprague-Dawley male rats (200–350 gm). Upon recovery from halothane anesthesia each rat received one of the following: 1) a directly acting cholinergic agonist (arecoline or nicotine); 2) a cholinesterase inhibitor, diethyi-p-nitrophenylphosphate (paraoxon), diisopropylfluorophosphate (DFP), neostigmine, or physostigmine; or 3) a central nervous system convulsant (pentylenetetrazol or strychnine).
Each drug was administered i. v. in logarithmic cumulative doses until the animal exhibited tremors, major motor or cortical EEG seizures, and/or died. All of the cholinergic agonists, including the ChEIs, induced motor tremors. Nicotine produced convulsions, observed in the EEG and gross behavior, while arecoline did not cause cortical EEG or gross behavioral seizures but did produce aberrant body movements. Neostigmine, even in supralethal doses, did not elicit motor or EEG seizures. Physostigmine, in sublethal doses, caused abnormal motor movements with EEG desynchronization. Supralethal doses of physostigmine or the irreversible ChEI paraoxon produced EEG convulsive patterns. Sublethal doses of DFP yielded similar effects. The ChEI seizure activity was partially antagonized by atropine. The nicotinic antagonists mecamylamine, pempidine, or trimethidinium did not alter the ChEI-induced EEG seizure patterns. Pentylenetetrazol produced both gross behavioral and EEG seizures, while strychnine in convulsant doses produced only EEG desynchronization. Supralethal doses of strychnine did induce EEG seizures.
Midazolam was an effective anticonvulsant against all of the convulsants, especially when the induced EEG seizures were recorded in ventilated animals. Nicotine-induced seizures were not only not antagonized by atropine, but were enhanced. Since atropine partially antagonized ChEI induced seizures, it is concluded that both a muscarinic cholinergic as well as a non-cholinergic mechanism is involved.
A comparison was made between diazepam and midazolam given i. m. in antagonizing 2 x LD50 of s. c. paraoxon in the presence of 10 mg/kg atropine. Both benzodiazepines were effective in reducing paraoxon induced seizures and death. However, midazolam was more potent.
KeywordsMuscarinic Receptor Sublethal Dose Cholinergic Agonist Motor Seizure Muscarinic Receptor Binding
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