Chronic effects of paraoxon on transmitter release and the synaptic contribution to tolerance

The chronic effects of sublethal injections of the cholinesterase inhibitor, paraoxon, on transmitter release were examined in the rat. Rats were chronically treated daily with the organophosphate, paraoxon (0.3 mg/kg b.wt.), that is known to inhibit acetylcholinesterase irreversibly. Severe symptoms of intoxication were evident in animals during the first few days of treatment but by day 11 the symptoms disappeared despite continued treatment and depression in acetylcholinesterase. Intracellular recording techniques were used to determine if the observed behavioral changes to chronic treatment could be correlated with changes in neuromuscular transmission. Measurements of MEPPs demonstrated that tolerance could not be attributed to a decrease in postsynaptic sensitivity. Measurements of EPPs, quantal release and binomial statistical parameters demonstrated that tolerance can be correlated with presynaptic changes. Chronic treatment with paraoxon decreased transmitter release and this can be attributed to a decrease in the transmitter store and mobilization ability. It is suggested that the depression in quantal release at the neuromuscular junction and at cholinergic synapses could account for behavioral tolerance.