1. The effect of guanosine on L-[3H] glutamate uptake was investigated in brain cortical slices within physio-pathological range of glutamate(1-1000 microM). In these conditions, glutamate uptake was significantly enhanced in slices treated with 100 microM guanosine only at 100 and 300 microM glutamate (44 and 52%, respectively). 2. Evaluation of kinetic parameters showed that guanosine affected significantly only uptake Vmax (23%). 3. The guanosine withdrawal did not abolish its significant effect on glutamate uptake when 100 or 300 microM glutamate were used (an increase of 66 and 35%, respectively). 4. These results support the hypothesis of a protective role for guanosine during excitotoxic conditions when glutamate levels are enhanced (e.g. brain ischemia and seizures), possibly by activating glutamate uptake. Moreover, our results may contribute to understand the antiexcitotoxic mechanism of guanosine on glutamate transport, giving new information concerning its mechanism of action.