title: Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil.
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 microM) 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 microM) 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 microM) and dl-fenfluramine (1-5 microM), 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 microM), 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.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ferraro
authors.forename: K
authors.initials: K
authors.lastname: Fuxe
authors.forename: S
authors.initials: S
authors.lastname: Tanganelli
authors.forename: M
authors.initials: M
authors.lastname: Fernandez
authors.forename: F A
authors.initials: FA
authors.lastname: Rambert
authors.forename: T
authors.initials: T
authors.lastname: Antonelli
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology; D008297:Male; D000077408:Modafinil; D017374:Paroxetine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D005277:Fenfluramine; D000077408:Modafinil; D017374:Paroxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors