Neurochemical studies showed that indomethacin is a noncompetitive inhibitor of the mouse cortical synaptosomal uptake of [3H]GABA with a Ki of 0.7 mM. Indomethacin also displaced [3H]flunitrazepam and [3H]GABA binding to washed cortical membranes in a competitive manner with IC50 values of 0.18 and 0.55 mM, respectively. It binds to the benzodiazepine receptors with the same characteristics as an inverse agonist and to the GABAA receptors as an antagonist. Behavioral studies showed that indomethacin dose-dependently increased the durations of loss of righting reflex induced by either diazepam or pentobarbitone, decreased rota-rod treading times and effectively prevented generalized seizures induced by pentylenetetrazole, bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate or maximal electroshock treatment. It is concluded that these effects of indomethacin are probably a result of GABA uptake inhibition. The present findings may explain some side effects of indomethacin on the central nervous system, such as impairment of psychomotor functions.