Abstract

Extracellular recording techniques have been used in the guinea pig hippocampal slice preparation to investigate the electrophysiological actions of the organophosphate (OP) anticholinesterase soman. When applied at a concentration of 100 nM, soman induced epileptiform activity in the CA1 region in approximately 75% of slices. This effect was mimicked by the anticholinesterases paraoxon (1 and 3 μM), physostigmine (30 μM), and neostigmine (30 μM), thus providing indirect evidence that the epileptiform response was mediated by elevated acetylcholine levels. Soman-induced bursting was inhibited by the muscarinic receptor antagonists atropine (concentrations tested, 0.1-10 μM), telenzepine (0.03-3 μM), AF-DX116 [11-(2-[(diethylamino)methyl]-1-piperidinyl acetyl)-5,11-dihydro-6H-pyrido 92.b-b) (1,4)-benzodiazepin-6-one] (0.3-300 μM), and biperiden (0.1-10 μM) and by the benzodiazepine anticonvulsants diazepam (3-30 μM) and midazolam (3-30 μM), but it was not inhibited by the nicotinic antagonists mecamylamine (30 μM) and methyllycaconitine (300 nM). In contrast to soman-induced epileptiform activity, bursting induced by the K⁺ channel blocker 4-aminopyridine (30 μM), the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (30 nM) or perfusion with low Mg²⁺ buffer was insensitive to atropine (10 μM). The ability of muscarinic antagonists and benzodiazepines to inhibit soman-induced epileptiform activity is in accordance with the in vivo pharmacology of soman-induced seizures and suggests that the guinea pig hippocampal slice preparation may provide a useful tool for the evaluation of novel anticonvulsant therapies for the treatment of seizures related to OP poisoning.