THE VIGILANCE PROMOTING DRUG MODAFINIL INCREASES DOPAMINE RELEASE IN THE RAT NUCLEUS-ACCUMBENS VIA THE INVOLVEMENT OF A LOCAL GABAERGIC MECHANISM

The present in vivo microdialysis study demonstrated that the subcutan eous 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-caud al 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 nu cleus accumbens with the GABA(B) receptor antagonist phaclofen (beta-p -chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 mu M), the GABA(A ) agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 mu M) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl -nipecotic acid) (0.1 mu M), whereas it was increased by the GABA(B) r eceptor )-baclofen[beta-(p-chlorophenyl-gamma-aminobutyric acid)](10 m u M) In addition, the modafinil-induced increase of dopamine release w as 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 loc al GABAergic transmission, which leads to a reduction of GABA(A) recep tor signaling on the dopamine terminals.