A comparison of the effects of acute and chronic cholinesterase inactivation on spontaneous transmitter release

The irreversible inhibitor of acetylcholinesterase (AChE), paraoxon, when given in vivo to rats in a single injection (0.23 mg/kg s.c.) raised the miniature endplate potential (MEPP) frequency to values greater than 3 times control levels in 34% of the fibers in the rat phrenic nerve-hemidiaphragm preparation. The elevated MEPP frequencies were observed in areas of extensive muscle twitching and were associated with high frequencies of giant MEPPs. Following 3 daily injections of paraoxon; the overall MEPP frequency was reduced below control levels, the frequency of giant MEPPs returned to normal, and a greater percentage of fibers showed no spontaneous activity. This depressant effect of chronic AChE inhibition on the overall MEPP frequency diminished during 1-2 weeks of daily paraoxon treatment (0.12 mg/kg s.c. paraoxon/day). After one week of recovery from 14 daily paraoxon injections (0.12 mg/kg, 1 injection/day), the original response to a single injection (0.23 mg/kg) was restored. In an attempt to determine whether paraoxon exerts its effects on spontaneous release by depolarizing the presynaptic terminal, the effect of increases in the potassium concentration on the MEPP and giant potential frequency were examined in control (saline injection) preparations, and preparations treated with 1 or 3 daily injections of paraoxon. The results suggest that paraoxon does not act by reducing the presynaptic membrane potential, but may interact more directly with the mechanism(s) responsible for regulating the release of MEPPs and giant MEPPs.