Impact of Astroglial Connexins on Modafinil Pharmacological Properties

Abstract

Modafinil is a non-amphetaminic wake-promoting compound used as therapy against sleepiness and narcolepsy. Its mode of action is complex, but modafinil has been recently proposed to act as a cellular-coupling enhancer in glial cells, through modulation of gap junctions constituted by connexins. The present study investigated in mice the impact of connexins on the effects of modafinil using connexin inhibitors. Modafinil was administered alone or combined with inhibitors of astrocyte connexin, meclofenamic acid, or flecainide, respectively, acting on Cx30 and Cx43. Sleep-wake states were monitored in wild-type and narcoleptic orexin knockout mice. A spontaneous alternation task was used to evaluate working memory in wild-type mice. The effects of the compounds on astroglial intercellular coupling were determined using dye transfer in acute cortical slices. Meclofenamic acid had little modulation on the effects of modafinil, but flecainide enhanced the wake-promoting and pro-cognitive effects of modafinil. Co-administration of modafinil/flecainide resulted in a marked decrease in the number and duration of direct transitions to rapid eye movement sleep, which are characteristic of narcoleptic episodes in orexin knockout mice. Furthermore, modafinil enhanced the connexin-mediated astroglial cell coupling, whereas flecainide reduced it. Finally, this modafinil-induced effect was reversed by co-administration with flecainide. Our study indicates that flecainide impacts the pharmacological effects of modafinil, likely through the normalization of Cx30-dependent gap junctional coupling in astroglial networks. The enhancement of the wake-promoting, behavioral, and cognitive outcomes of modafinil demonstrated here with flecainide would open new perspectives in the management of sleep disorders such as narcolepsy. A commentary on this article appears in this issue on page 1175. This study focuses on the pharmacological properties of modafinil, a wake-promoting compound used worldwide in sleep and cognitive disorders. The wake-promoting and pro-cognitive effects of modafinil have been linked with complex monoaminergic and gabaergic neuronal mechanisms. Recently, effects of modafinil on astroglial connexins also have drawn attention. Although modafinil improves behavioral activity and excessive daytime sleepiness, it does not prevent the occurrence of cataplexy, a major syndrome of narcolepsy. We found in mice that an astroglial-connexin-30 inhibitor impacts the pharmacological properties of modafinil by enhancing its awakening and pro-cognitive activities and by decreasing the cataplexy-like phenotype in orexin-knockout narcoleptic mice. Our findings thus open new perspectives in the management of sleep and cognitive disorders.