The action of anticonvulsant drugs, phenytoin, diazepam, clonazepam and phenobarbitone, was tested on the release of [ 14C]-GABA from tissue slices of rat cerebral cortex. All drugs caused a significant dose-dependent depression of the 33mM-K +-evoked release of [ 14C]-GABA but had little effect on the resting release of [ 14C]-GABA, except at high concentrations. The IC 50 values for inhibition of K +-evoked release of [ 14C]-GABA were 4.7 × 10 −5, 7 × 10 −5, 28 × 10 −5 and 7.9 × 10 −4M for diazepam, clonazepam, phenytoin and phenobarbitone respectively. Trifluoperazine also caused a similar and complete inhibition of [ 14C]-GABA release with an IC 50 of 1 × 10 −5M. The effect of diazepam and trifluoperazine were additive. The inhibition by trifluoperazine could be overcome by addition of exogenous calmodulin, whereas that of diazepam, phenytoin or phenobarbitone was not overcome. It is proposed that the anticonvulsants tested inhibit calcium-dependent transmitter release at a site distal to the formation of a calcium-calmodulin complex, which is presumably activated by this complex. Trifluoperazine, on the other hand, acts by reducing the availability of calmodulin.