Thomas Thorne
ABSTRACT
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 study, modafinil (0.3-30 muM) increased electrically evoked, but not spontaneous, serotonin ([(3)H]5-HT) flux from cortical slices in a concentration-dependent manner. , while the indirect serotonin agonist dl-fenfluramine (1-15 muM) improved both spontaneous and evoked [(3)H]5-HT efflux.
The effects of modafinil were more pronounced when paroxetine blocked 5-HT reuptake. Unlike paroxetine (0.3-3 muM) and dl-fenfluramine (1-5 muM), modafinil failed to influence the absorption of [(3)H]5-HT. In the in vivo study, modafinil (3-100 mg/kg i.p.) increased dialysate levels of 5-HT, and the maximum effect was already achieved at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) induced an increase in 5-HT levels that was significantly greater than that shown by modafinil at 30 mg/kg.
In the presence of paroxetine (3 µM), the effect of modafinil at 30 mg/kg was greater than that observed in the absence of 5-HT reuptake inhibition. Finally, in the presence of the selective 5-HT(1A) receptor agonist, 8-OH-DPAT, modafinil at 100 mg/kg failed to affect dialysate 5-HT levels.These results demonstrate that modafinil regulates cortical serotonergic transmission and suggest that the drug acts preferentially by amplifying electro-neurosecretory coupling mechanisms and through mechanisms that do not involve the reuptake process.