The vigilance-promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and posterior hypothalamus of the conscious rat: prevention by local blockade of the GABAA receptor

ABSTRACT

The effects of modafinil on glutamatergic and GABAergic transmission in the medial preoptic area (MPA) and posterior hypothalamus (PH) of rats are analyzed. Modafinil (30-300 mg/kg) increased glutamate and decreased GABA levels in MPA and PH. Local perfusion with the GABAA agonist muscimol (10 microM) was reduced, while the GABAA antagonist bicuculline (1 microM and 10 microM) increased glutamate levels. The increase in glutamate levels induced by modafinil (100 mg/kg) was antagonized by local perfusion with bicuculline (1 microM).

When glutamate levels were increased by local perfusion with the glutamate uptake inhibitor L-trans-PDC (0.5 mM), modafinil produced a further improvement in glutamate levels. Modafinil (1-33 microM) failed to affect [3H]glutamate uptake in synaptosomes and hypothalamic slices. These findings show that modafinil increases glutamate and decreases GABA levels in MPA and PH. The evidence that bicuculline counteracts the modafinil-induced increase in glutamate levels reinforces the evidence for an inhibitory GABA/glutamate interaction in the aforementioned regions that control the sleep-wake cycle.