Studies on the Mechanism of Action of Avermectin B₁a: Stimulation of Release of γ‐Aminobutyric Acid from Brain Synaptosomes

Avermectin B 1 a, a novel macrocyclic lactone antiparasitic agent, causes a marked and sustained increase of γ‐aminobutyric acid release from rat brain synaptosomes. A concentration of 8‐10 μM of avermectin B 1 a produced the maximal effect (310 ± 30% of the control), while the half‐maximal level was achieved at 2‐3 μM. The drug also stimulated γ‐aminobutyric acid release (251 ± 11% of the basal level) from synaptosomes in calcium‐free medium, which was 28 ± 4% lower than that in the 1.8 m m ‐Ca 2+ medium. The compound did not, however, affect the synaptosomal release of glutamate. At the lobster neuromuscular junction, avermectin B 1 a reduced the input resistance of muscle fibers in control Ringer's solution as well as in Ringer's solution in which Co 2+ was substituted for Ca 2+ . This observation is in accord with the Ca 2+ independent stimulation of γ‐aminobutyric acid release seen with synaptosomes. A good correlation between antiparasitic activity and γ‐aminobutyric acid‐releasing activity has been found among various derivatives of avermectin B 1 a, which suggests that the ability of the drug to release this neurotransmitter may be the basis of its antiparasitic action.