Xenopus oocytes injected with poly(A)+ RNA from rat cerebral cortex express functional gamma-aminobutyric acid (GABA)A receptors with electrical properties and pharmacology similar to those of receptors studied in situ. Fenamates, a class of nonsteroidal anti-inflammatory drugs (NSAIDs), had a dual effect on GABA-activated membrane current responses. Currents elicited by low concentrations of GABA were potentiated, whereas currents elicited by high concentrations of GABA were inhibited. The levels of the two effects varied among fenamates. For example, 10 microM mefanamic acid potentiated 10 microM GABA responses by approximately 300% (EC50 approximately 5 microM) and inhibited maximal responses by 30% (IC50 approximately 30 microM). In contrast, 10 microM niflumic acid potentiated 10 microM GABA responses by only 30% (EC50 approximately 10 microM) and inhibited maximal responses by 60% (IC50 approximately 7 microM). Preliminary structure-activity studies suggested that modulatory activity is dependent on the preferred conformations of fenamate molecules and on specific phenyl-ring substitutions. Thirteen other NSAIDs (all prostaglandin synthesis inhibitors) were likewise assayed for effects on GABA-activated currents. Of these, only the salicyclic acid diflunisal induced comparable potentiation and inhibition. Our experiments raise two interesting possibilities: that fenamates could serve as lead structures in the development of novel GABAA receptor modulators and that fenamates might affect GABAA receptor function at a normal clinical dosage.