Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil

The present in vitro and in vivo studies examined the effects of modafinil on serotonergic transmission in the rat frontal cortex. In the in vitro stu dy modafinil (0.3-30 mu M) increased electrically-evoked, but not spontaneo us, serotonin ([H-3]5-HT) efflux from cortical slices in a concentration-de pendent manner while the indirect serotonin agonist dl-fenfluramine (1-15 m u M) enhanced both spontaneous and evoked [3H]5-HT efflux. The effects of m odafinil were more pronounced when the 5-HT reuptake was blocked by paroxet ine. Contrary to paroxetine (0.3-3 mu M) and dl-fenfluramine (1-5 mu M), mo dafinil failed to influence the [H-3]5-HT uptake. In the in vivo study moda finil (3-100 mg/kg i.p.) increased 5-HT dialysate levels, the maximal effec t being already reached at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) ind uced an increase in 5-HT levels which was significantly higher than that di splayed by modafinil at 30 mg/kg. In the presence of paroxetine (3 mu M), t he effect of modafinil at 30 mg/kg was higher than that observed in the abs ence of 5-HT reuptake inhibition. Finally, in the presence of the selective 5-NT1A receptor agonist 8-OH-DPAT, modafinil at 100 mg/kg failed to affect 5-HT dialysate levels. These results demonstrate that modafinil regulates cortical serotonergic tr ansmission and suggest that the drug preferentially acts by amplifying the electro-neurosecretory coupling mechanisms and via mechanisms which do not involve the reuptake process. (C) 2000 Elsevier Science Ltd. All rights res erved.