Impact of Astroglial Connexins on Modafinil Pharmacological Properties

Overview

Journal Sleep

Publisher Oxford University Press

Specialty Psychiatry

Date 2016 Apr 20

PMID 27091533

Citations 25

Authors

Adeline Duchene

Magali Perier

Yan Zhao

Xinhe Liu

Julien Thomasson

Frederic Chauveau

Christophe Pierard

Didier Lagarde

Christele Picoli

Tiffany Jeanson

Franck Mouthon

Yves Dauvilliers

Christian Giaume

Jian-Sheng Lin

Mathieu Charveriat

Affiliations

Soon will be listed here.

Abstract

Study Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Commentary: A commentary on this article appears in this issue on page 1175.

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References

Davidson J, Baumgarten I . Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communication. Structure-activity relationships. J Pharmacol Exp Ther. 1988; 246(3):1104-7. View

Kopp C, Petit J, Magistretti P, Borbely A, Tobler I . Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice. Neuropharmacology. 2002; 43(1):110-8. DOI: 10.1016/s0028-3908(02)00070-9. View

Wisor J, Nishino S, Sora I, Uhl G, Mignot E, Edgar D . Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001; 21(5):1787-94. PMC: 6762940. View

Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Guldenagel M . Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem. 2002; 383(5):725-37. DOI: 10.1515/BC.2002.076. View

Giaume C, Theis M . Pharmacological and genetic approaches to study connexin-mediated channels in glial cells of the central nervous system. Brain Res Rev. 2009; 63(1-2):160-76. DOI: 10.1016/j.brainresrev.2009.11.005. View

Escartin C, Rouach N . Astroglial networking contributes to neurometabolic coupling. Front Neuroenergetics. 2013; 5:4. PMC: 3636502. DOI: 10.3389/fnene.2013.00004. View

Robertson Jr P, Hellriegel E . Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003; 42(2):123-37. DOI: 10.2165/00003088-200342020-00002. View

Lopez R, Dauvilliers Y . Pharmacotherapy options for cataplexy. Expert Opin Pharmacother. 2013; 14(7):895-903. DOI: 10.1517/14656566.2013.783021. View

Mazzarino M, Botre F . A fast liquid chromatographic/mass spectrometric screening method for the simultaneous detection of synthetic glucocorticoids, some stimulants, anti-oestrogen drugs and synthetic anabolic steroids. Rapid Commun Mass Spectrom. 2006; 20(22):3465-76. DOI: 10.1002/rcm.2729. View

10.

Beracochea D, Celerier A, Peres M, Pierard C . Enhancement of learning processes following an acute modafinil injection in mice. Pharmacol Biochem Behav. 2003; 76(3-4):473-9. DOI: 10.1016/j.pbb.2003.09.007. View

11.

Franco-Perez J, Paz C . Quinine, a selective gap junction blocker, decreases REM sleep in rats. Pharmacol Biochem Behav. 2009; 94(2):250-4. DOI: 10.1016/j.pbb.2009.09.003. View

12.

Cruciani V, Mikalsen S . The vertebrate connexin family. Cell Mol Life Sci. 2006; 63(10):1125-40. PMC: 11136263. DOI: 10.1007/s00018-005-5571-8. View

13.

Somani P . Antiarrhythmic effects of flecainide. Clin Pharmacol Ther. 1980; 27(4):464-70. DOI: 10.1038/clpt.1980.65. View

14.

Beck P, Odle A, Wallace-Huitt T, Skinner R, Garcia-Rill E . Modafinil increases arousal determined by P13 potential amplitude: an effect blocked by gap junction antagonists. Sleep. 2008; 31(12):1647-54. PMC: 2603487. DOI: 10.1093/sleep/31.12.1647. View

15.

Beracochea D, Jaffard R . Impairment of spontaneous alternation behavior in sequential test procedures following mammillary body lesions in mice: evidence for time-dependent interference-related memory deficits. Behav Neurosci. 1987; 101(2):187-97. DOI: 10.1037//0735-7044.101.2.187. View

16.

Chemelli R, Willie J, Sinton C, Elmquist J, Scammell T, Lee C . Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999; 98(4):437-51. DOI: 10.1016/s0092-8674(00)81973-x. View

17.

Parmentier R, Anaclet C, Guhennec C, Brousseau E, Bricout D, Giboulot T . The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochem Pharmacol. 2007; 73(8):1157-71. DOI: 10.1016/j.bcp.2007.01.002. View

18.

Qu W, Huang Z, Xu X, Matsumoto N, Urade Y . Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci. 2008; 28(34):8462-9. PMC: 6671058. DOI: 10.1523/JNEUROSCI.1819-08.2008. View

19.

Picoli C, Nouvel V, Aubry F, Reboul M, Duchene A, Jeanson T . Human connexin channel specificity of classical and new gap junction inhibitors. J Biomol Screen. 2012; 17(10):1339-47. DOI: 10.1177/1087057112452594. View

20.

Stone E, Cotecchia S, Lin Y, Quartermain D . Role of brain alpha 1B-adrenoceptors in modafinil-induced behavioral activity. Synapse. 2002; 46(4):269-70. DOI: 10.1002/syn.10127. View