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NEUROPHARMACOLOGY

A Guinea Pig Hippocampal Slice Model of Organophosphate-Induced Seizure Activity

Biomedical Sciences, Dstl, Porton Down, Salisbury, Wiltshire, United Kingdom

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.

Address correspondence to: Dr. P. K. Harrison, Biomedical Sciences, Dstl, Bldg. 04, Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. E-mail: pkharrison{at}dstl.gov.uk

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