The effects of the vigilance promoting drug modafil were studied ex vivo (100 mg/kg; i.p.) and in vitro (10-1000 μM modafinil) on the synthesis of [ 3 H]γ-aminobutyric acid ([ 3 H]GABA) and [ 3 H]glutamate from [ 3 H]glutamine within the rat hypothalamus. No effects of modafinil were observed on the overall synthesis of these neurotransmitters nor, in vitro (1-33 μM modafinil) on other parameters related to the compartmentalization of their synthesis (glutamate decarboxylase and phosphate-activated glutaminase activities, and [ 3 H]glutamine uptake). It is suggested on these grounds, that the modafinil-induced reductions and increases in regional GABA and glutamate extracellular levels respectively using in vivo microdialysis may be a consequence of an indirect effect of modafinil on these neurons.