Effects of Modafinil on Clonic Seizure Threshold Induced by Pentylenetetrazole in Mice: Involvement of Glutamate, Nitric oxide, GABA, and Serotonin Pathways

Abstract

Epilepsy is the third most common chronic brain disorder. Modafinil is an awakening agent approved for narcolepsy. In addition to its clinical uses some reports revealed that modafinil was associated with some alterations in seizure threshold. The purpose of this study was to clarify the effect of acute administration of modafinil in clonic seizure threshold (CST) induced by pentylenetetrazole in mice and the involvement of glutamate, nitric oxide, gamma amino butyric acid (GABA), and serotonin systems in this feature. Modafinil at 80 and 150 mg/kg showed anti- and pro-convulsant effects respectively and expressed maximum anti- and pro-convulsant activities at 30 min after injection. Both modulatory effects were blunted by pretreatment of l-NAME [nonspecific nitric oxide synthase (NOS) inhibitor; 10 mg/kg, i.p.], 7-nitroindazole (a neuronal NOS inhibitor; 40 mg/kg, i.p.), and aminoguanidine (an inducible NOS inhibitor; 50 mg/kg, i.p.). Injection of the NOS precursor l-arginine (60 mg/kg, i.p.) before modafinil did not change the anti-convulsant effect, while thoroughly reversed the pro-convulsant one. Our experiments displayed that administration of diazepam (a GABA_A receptor agonist; 0.02 mg/kg, i.p.) and MK-801 (a NMDA receptor antagonist; 0.05 mg/kg, i.p.) before different doses of modafinil significantly increased CST. Finally, pretreatment of citalopram (a selective serotonin reuptake inhibitor; 0.1 mg/kg, i.p.) did not modify the convulsant activities of modafinil. Therefore, nitric oxide system may mediate anti-convulsant activity, while glutamate, nitric oxide, and GABA pathways may involve in pro-convulsant property. Serotonin receptors have no role on convulsant effects of modafinil.