ACETYLCHOLINESTERASE REACTIVATORS ANTAGONIZE EPILEPTIFORM BURSTING INDUCED BY PARAOXON IN GUINEA-PIG HIPPOCAMPAL SLICES

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Abstract
The electrophysiological actions of paraoxon, an irreversible blocker of acetylcholinesterase, and their antagonism by a series of organophosphate cholinesterase reactivators, were studied in area CA1 of the quinea pig hippocampus in vitro. To avoid indirect effects elicited by excitation of CA3 neurons, the CA2/3 regions were removed routinely before the recording of extracellular field potentials in CA1. Under these conditions, paraoxon (1 .mu.M) induced regular burst activity (rate, 2-10/min; amplitude, 0.2-1 mV; duration, 100-500 msec). The antagonism of this burst activity by atropine (0.3-1.0 .mu.M) and pirenzepine (1.0 .mu.M) suggested the involvement of muscarinic cholinoceptors in the mediation of this response. The reduction in frequency of paraoxon-induced bursting by the cholinesterase reactivators was taken as an index of their efficacies. The four oxime compound tested were all active in the low micromolar range (rank order of potencies: obidoxime > HGG 12 = HLo 7 > HI 6). In experiments without paraoxon, these oximes did not depress either evoked population spikes in normal artificial cerebrospinal fluid or bursts induced by superfusion with Mg++-free artificial cerebrospinal fluid. Thus, an unspecific inhibitory effect of oximes can be excluded. It is concluded that the in vitro hippocampus provides a suitable system for the quantitative electrophysiological evaluation of cholinesterase reactivators in the central nervous system.