A guinea pig hippocampal slice model of organophosphate-induced seizure activity.
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 microM), physostigmine (30 microM), and neostigmine (30 microM), 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 microM), telenzepine (0.03-3 microM), 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 microM), and biperiden (0.1-10 microM) and by the benzodiazepine anticonvulsants diazepam (3-30 microM) and midazolam (3-30 microM), but it was not inhibited by the nicotinic antagonists mecamylamine (30 microM) and methyllycaconitine (300 nM). In contrast to soman-induced epileptiform activity, bursting induced by the K(+) channel blocker 4-aminopyridine (30 microM), the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (30 nM) or perfusion with low Mg(2+) buffer was insensitive to atropine (10 microM). 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.
Harrison
Patrick K
PK
Biomedical Sciences, DSTL, Bldg. 04, Porton Down, Salisbury, Wiltshire SP4 0JQ, UK. pkharrison@dstl.gov.uk
Sheridan
Robert D
RD
Green
A Chris
AC
Scott
Iain R
IR
Tattersall
John E H
JE
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009924:Organ Culture Techniques; D010755:Organophosphates / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D012999:Soman / Q000037:antagonists & inhibitors / Q000494:pharmacology
D010755:Organophosphates; D001285:Atropine; D012999:Soman