Abstract
RationaleSeizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies.ObjectivesThe aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)—carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA).MethodsAnticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects.ResultsIntraperitoneal injection of 75 mg kg−1 of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg−1 of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg−1 dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg−1) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT.ConclusionsEnhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.
Highlights
Modafinil is wakepromoting medication approved for the treatment of narcolepsy, shift work sleep problems, and obstructive sleep apnea (Ballon and Feifel 2006; Minzenberg and Carter 2008)
Intraperitoneal injection of 75 mg kg−1 of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg−1 of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB
Because modafinil is a dopamine transporter (DAT) blocker, we compared the anticonvulsant effects of modafinil and its two metabolites to the prototypical DAT blocker—GBR 12909
Summary
Modafinil (diphenylmethylsulfinylacetamide) is wakepromoting medication approved for the treatment of narcolepsy, shift work sleep problems, and obstructive sleep apnea (Ballon and Feifel 2006; Minzenberg and Carter 2008). Modafinil is reported to affect many central neurotransmitter systems: dopamine, norepinephrine, 5-hydroxytryptamine, glutamate, GABA, histamine, and orexin. Initial preclinical studies indicated that stimulant effects of modafinil are distinct from those of amphetamine and may not involve dopamine systems (Duteil et al 1990; Simon et al 1995). Modafinil has a number of nondopaminergic effects which include activation of α1 adrenergic receptors (Duteil et al 1990), enhancement of 5-hydroxytryptamine function (Ferraro et al 2000), inhibition of GABA release (Ferraro et al 1997, 1998), and stimulation of glutamate and histamine release (Ferraro et al 1999; Ishizuka et al 2003)
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