The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.