On the development of behavioral tolerance to organophosphates. II: Neurophysiological aspects.
In a recent study (9) it was found in rats that chronic treatment with the irreversible cholinesterase inhibitors DFP or soman led to behavioral tolerance in the case of DFP, but not in the case of soman. Biochemically, no explanation was found for this difference between these two inhibitors. Notably, chronic administration of each of these inhibitors did not affect the availability of the nicotinic receptors at the motor endplate, in spite of very low cholinesterase activity. In an attempt to explain the different effects of these inhibitors a neurophysiological approach seemed appropriate. The spontaneous quantal release of acetylcholine from diaphragm muscles in vitro from animals chronically treated with each inhibitor showed a similar trend; compared with controls the MEPP frequency was decreased, which was significant for DFP, and the MEPP amplitude was increased, which was significant for soman. Neuromuscular function of muscle strips obtained from both DFP- or soman-treated animals appeared significantly more sensitive to additional inhibitor added in vitro. This could simply be explained by the high preexisting level of cholinesterase inhibition, but seems in contrast with the phenomenon of tolerance.
Melchers
B P
BP
Medical Biological Laboratory TNO, Rijswijk, The Netherlands.
van Helden
H P
HP
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D004361:Drug Tolerance; D004594:Electrophysiology; D007531:Isoflurophate / Q000494:pharmacology*; D008297:Male; D009469:Neuromuscular Junction / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D007531:Isoflurophate; D012999:Soman; D000110:Acetylcholinesterase