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Release of excitatory transmitter from boutons on crayfish nerve terminals was inhibited by (R,S)-baclofen, an agonist at GABAB receptors. Baclofen had no postsynaptic actions as it reduced quantal content without affecting quantal amplitude. The effect of baclofen increased with concentration producing 18% inhibition at 10 microM; EC50, 50% inhibition at 30 microM; maximal inhibition, 85% at 100 microM and higher. There was no desensitization, even with 200 or 320 microM baclofen. Phaclofen, an antagonist at GABAB receptors, competitively antagonized the inhibitory action of baclofen (KD = 50 microM, equivalent to a pA2 = 4.3 +/- 0.1). Phaclofen on its own at concentrations below 200 microM had no effect on release, whereas at 200 microM phaclofen itself increased the control level of release by 60%, as did 2-hydroxy-saclofen (200 microM), another antagonist at GABAB receptors. This increase was evidently due to antagonism of a persistent level of GABA in the synaptic cleft, since the effect was abolished by destruction of the presynaptic inhibitory fiber, using intra-axonal pronase. We conclude that presynaptic GABAB receptors, with a pharmacological profile similar to that of mammalian GABAB receptors, are involved in the control of transmitter release at the crayfish neuromuscular junction.