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

Ferraro L, Fuxe K, Tanganelli S,
Fernandez M, Rambert FA, Antonelli T

Department of Experimental and Clinical Medicine,
Section of Pharmacology,
University of Ferrara, Ferrara, Italy
Neuropharmacology 2000 Oct 1; 39(11):1974-1983

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) efflux from cortical slices in a concentration-dependent manner while the indirect serotonin agonist dl-fenfluramine (1-15 muM) enhanced both spontaneous and evoked [(3)H]5-HT efflux. The effects of modafinil were more pronounced when the 5-HT reuptake was blocked by paroxetine. Contrary to paroxetine (0.3-3 muM) and dl-fenfluramine (1-5 muM), modafinil failed to influence the [(3)H]5-HT uptake. In the in vivo study modafinil (3-100 mg/kg i.p.) increased 5-HT dialysate levels, the maximal effect being already reached at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) induced an increase in 5-HT levels which was significantly higher than that displayed by modafinil at 30 mg/kg. In the presence of paroxetine (3 muM), the effect of modafinil at 30 mg/kg was higher 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 5-HT dialysate levels.These results demonstrate that modafinil regulates cortical serotonergic transmission and suggest that the drug preferentially acts by amplifying the electro-neurosecretory coupling mechanisms and via mechanisms which do not involve the reuptake process.
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