THE ability of modafinil (Modiodal®) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1= 0.77 ± 0.14; St2/St1ratio = 0.94 ± 0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1= 0.40 ± 0.05; St2/St1ratio = 0.60 ± 0.08). Modafinil (0.3–1 μM) prevented the glutamate-induced reduction of the St2/St1ratio (0.85 ± 0.11; 0.88 ± 0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons