The effects of local anesthetics on the synthesis, release, and degradation of gamma-aminobutyric acid (GABA) in rat brains were investigated. The addition of procaine, lidocaine, cocaine, or tetracaine did not alter either glutamic acid decarboxylase (GAD) activity or GABA transaminase (GABA-T) activity in vitro. Neither did the enzyme activities in rats with local anesthetic-induced convulsions differ from control values. Tetracaine inhibited high K+-evoked [2,3-3H]GABA release from synaptosomes of rat brain in a dose-dependent manner with a minimal effective concentration of 10(-4) M. Cocaine, lidocaine, and procaine also reduced the release, although they were less potent than tetracaine. The GABA release inhibitors in order of potency are tetracaine, cocaine, lidocaine, and procaine which correlates well with their relative toxicity as convulsants. These results suggest that local anesthetics reduce GABAergic activities by inhibiting the release of the neurotransmitter from the nerve terminals, and that inhibition of the GABA system may be involved in the mechanism of local anesthetic-induced convulsions.