Actions of avermectin B1a on GABA nerves

Avermectin B1a (AVM) is a macrolide derived from Streptomyces avermitilis. It possesses potent anthelmintic and insecticidal activities. It immobilizes nematodes by blocking the signal transmission from the central command interneurons to the peripheral motoneurons; this block can be reversed by the chloride ion channel blocker picrotoxin. The arthropods are paralyzed by AVM through drug inhibition of both inhibitory and excitatory postsynaptic potentials at the neuromuscular junctions. The mechanism of action is reduction of the muscle membrane resistance by opening the gamma-aminobutyric acid (GABA)-controlled chloride ion channels in the membrane--an action also inhibitable by picrotoxin. AVM has specific and high-affinity binding sites in the mammalian brain synaptic membrane. The sites are concentrated in the cerebellum and closely associated with the GABA-benzodiazepine receptor-chloride ion channel complex. GABA release from brain synaptosomes is specifically stimulated by AVM. The density of available postsynaptic GABA receptors is increased by AVM--a process which requires chloride ion and is inhibited by picrotoxin. AVM also stimulates benzodiazepine binding and potentiates the in vivo diazepam activity of muscle relaxation. These findings add up to a conclusive demonstration of the mechanism of AVM action as a potentiation of the GABA action. They also point out the research on GABA nerve in invertebrates as an attractive approach to chemotherapy against nematodes and insects and suggest AVM as a very useful tool in isolating GABA receptors and in-depth understanding of GABA function.