Variations in extracellular monoamines in the prefrontal cortex and medialhypothalamus after modafinil administration: a microdialysis study in rats

The role of brain amines in mediating the effects of the wake-promoting age nt modafinil, used in the treatment of sleepiness associated with narcoleps y is still uncertain. Therefore we studied the effects of modafinil on extr acellular serotonin (5-HT), dopamine (DA) and noradrenaline (NA), in rat pr efrontal cortex and in the medial hypothalamus area. Modafinil (128 mg/kg i .p,) significantly increased waking in the first 4h of EEG sleep recording. This cortical and behavioral activation was associated with an initial inc rease in extracellular 5-HT, DA and NA during the first 60 min following mo dafinil administration. In the prefrontal cortex, 5-HT release remained hig h for 3 h after modafinil administration. In contrast, in the hypothalamus, only NA release was enhanced while DA and 5-HT levels remained low. In a f irst step, modafinil may generate waking partly via cortical monoamine rele ase, particularly DA and 5-HT, and also hypothalamic NA. In a second step, maintenance of waking might depend on hypothalamic NA. (C) 2001 Lippincott Williams & Wilkins.