Acetylcholinesterase inhibitors used as insecticides, nematocides, acaricides, fungicides, etc., present a considerable environmental hazard to the health of agricultural workers and others. It is therefore necessary to fully understand the mode of action of these substances in blocking synaptic transmission so that effective treatments can be devised for those who are accidently poisoned. In our proposed studies the mode of action of representative anti-AChE pesticides from the organophosphate and carbamate families will be studied at the mammalian neuromuscular junction. Preliminary studies have shown that block of neuromuscular transmission by AChE inhibitors can be due to a depolarization of the postsynaptic membrane which occurs only while the nerve is being stimulated. The muscle responds normally to the first nerve stimulation in a train but subsequent stimulation has little or no effect. After the stimulation train is ended, the muscle rapidly returns to normal. Our hypothesis is that after block of AChE, the endplate potential is so large and so long that there is a build up of depolarization and a frequency dependent block of transmission. After the nerve activity ceases, the membrane quickly returns to normal due to normal due to the rapid diffusion of excess ACh from the endplate. In preliminary studies we have found that transmission may be restored after this transmission block, by using pharmacological procedures which reduce the amplitude and time constant of the endplate potential. These procedures include the reduction of calcium levels which in turn reduces the presynaptic release of ACh. Alternatively, the postsynaptic blockade of receptors by certain drug molecules also reverses the neuromuscular block induced by AChE inhibitors. We propose a detailed analysis of these therapeutic procedures and investigations which will provide useful information on their exact modes of action. The studies will measure both presynaptic and postsynaptic events and will also use a special apparatus where muscle contraction and compound action potential can be measured simultaneously.
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