Postsynaptic inhibition of invertebrate neuromuscular transmission by avermectin B1a

Abstract

The avermectins are a family of novel macrocyclic lactones which paralyze nematodes and insects. One highly potent member of this family, avermectin B1a, has been shown to block neuromuscular transmission in the lobster opener and stretcher muscles. Continuous superfusion of these muscles with the drug (6 microM) resulted in a rapid loss of intracellularly recorded inhibitory postsynaptic potentials. Amplitudes of excitatory potentials and membrane input resistance declined at a slower rate, with a similar time course (25-30 min). These effects were not reversed by prolonged washing. A 3-5 mV hyperpolarization was also observed, which was reversed to depolarization in low chloride lobster saline. Picrotoxin (20 microM) blocked the effects of avermectin B1a on excitatory postsynaptic potentials. Both gamma-aminobutyric acid (GABA) and avermectin B1a decreased the slope of current voltage curves in the stretcher muscle, reflecting an increase in membrane conductance. These changes were greatly reduced by application of bicuculline (50 microM) or picrotoxin (20 microM) Avermectin B1a had no effect on the "fast" axon excitatory electrical responses (glutaminergic) of the cockroach extensor tibiae muscle fibers which lack an inhibitory (GABAergic) input. It is concluded that at the lobster neuromuscular junction, avermectin B1a acts on the GABAergic synapse and lowers input resistance of the muscle membranes by causing an increase in chloride ion permeability.