Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic α1 and histaminergic H1 receptors in mice

Epilepsy is characterized by neuronal hyperexcitability and hypersynchronization. Disruption of electroencephalographically (EEG) synchronized epileptiform discharges may be a possible therapy for epilepsy. In the present study, to clarify the role of EEG desynchronization on epilepsy, we investigated the effect of modafinil, a potent wake-promoting substance with EEG desynchronization activity, on epilepsy in mice and clarified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) kindling models. Modafinil given at 22.5, 45, and 90 mg/kg, i.p. significantly decreased the incidence of tonic hindleg extension in MES seizure models, and protected against PTZ-induced convulsive behaviors in a dose-dependent manner. In addition, modafinil at 180 mg/kg exerted an antiepileptic effect in the MES model; however, at the same dosage it increased the seizure stage in the PTZ-kindling model. The antiepileptic effect in both MES and PTZ models was antagonized by the adrenergic alpha(1) receptor antagonist terazosin, but not by the adrenergic alpha(2) receptor antagonist yohimbine or by dopaminergic receptor antagonists, SCH-23390 (for D(1) receptors) and haloperidol (for D(2) ones). Pyrilamine, a histaminergic H(1) receptor antagonist, counteracted the antiepileptic action of modafinil in the PTZ induced-kindling model, but not in the MES seizure model. Taken together, the present findings indicate that modafinil exerted its antiepileptic effect via adrenergic alpha(1) and histaminergic H(1) receptors, and might be of potential use in the treatment of epilepsy.

[1]  M. N. Shouse,et al.  Sleep and arousal mechanisms in experimental epilepsy: epileptic components of NREM and antiepileptic components of REM sleep. , 2004, Mental retardation and developmental disabilities research reviews.

[2]  B. Fredholm,et al.  Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. , 1999, Pharmacological reviews.

[3]  P. Luppi,et al.  Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study. , 2004, Sleep.

[4]  Jon T. Willie,et al.  Narcolepsy in orexin Knockout Mice Molecular Genetics of Sleep Regulation , 1999, Cell.

[5]  M. Jouvet,et al.  Hypothalamo‐preoptic Histaminergic Projections in Sleep‐Wake Control in the Cat , 1994, The European journal of neuroscience.

[6]  S. Nicolaidis,et al.  Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats , 2001, Neuroreport.

[7]  S. Krahl,et al.  Locus Coeruleus Lesions Suppress the Seizure‐Attenuating Effects of Vagus Nerve Stimulation , 1998, Epilepsia.

[8]  H. Frey,et al.  Histamine in brain — its role in regulation of seizure susceptibility , 1991, Epilepsy Research.

[9]  D. Weinshenker,et al.  The role of catecholamines in seizure susceptibility: new results using genetically engineered mice. , 2002, Pharmacology & therapeutics.

[10]  R. Leurs,et al.  Therapeutic potential of histamine H3 receptor agonists and antagonists. , 1998, Trends in pharmacological sciences.

[11]  Xihong Lin,et al.  Relationship of interictal epileptiform discharges to sleep depth in partial epilepsy. , 1997, Electroencephalography and clinical neurophysiology.

[12]  Li-Hong Shi,et al.  Deep brain stimulation of the substantia nigra pars reticulata exerts long lasting suppression of amygdala-kindled seizures , 2006, Brain Research.

[13]  C. Sánchez,et al.  Anticonvulsant and antiepileptogenic effects of GABAA receptor ligands in pentylenetetrazole-kindled mice , 2004, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  Y. Urade,et al.  Arousal effect of orexin A depends on activation of the histaminergic system , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Yamatodani,et al.  Modafinil increases histamine release in the anterior hypothalamus of rats , 2003, Neuroscience Letters.

[16]  Zhi-Li Huang,et al.  Orexin A promotes histamine, but not norepinephrine or serotonin, release in frontal cortex of mice , 2005, Acta Pharmacologica Sinica.

[17]  Y. Urade,et al.  An adenosine A receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats. , 2005, Journal of neurochemistry.

[18]  N. Bowery,et al.  Effects of GABAB receptor antagonism on the development of Pentylenetetrazol-induced kindling in mice , 1998, Brain Research.

[19]  D. Morilak,et al.  Changes in Tyrosine Hydroxylase mRNA Expression in the Rat Locus Coeruleus Following Acute or Chronic Treatment with Valproic Acid , 2000, Neuropsychopharmacology.

[20]  F. Rambert,et al.  Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. , 1990, European journal of pharmacology.

[21]  S. Trottier,et al.  Role of noradrenergic ascending system in extinction of epileptic phenomena. , 1986, Advances in neurology.

[22]  N. Hashimoto,et al.  Deep brain stimulation of the posterior hypothalamus activates the histaminergic system to exert antiepileptic effect in rat pentylenetetrazol model , 2007, Experimental Neurology.

[23]  R. Drucker-Colín,et al.  Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats , 2007, Behavioural Brain Research.

[24]  Yoshihiro Urade,et al.  Prostaglandins and adenosine in the regulation of sleep and wakefulness. , 2007, Current opinion in pharmacology.

[25]  Wei-Min Qu,et al.  Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  F. Romanelli,et al.  Clinical Effects and Management of Methamphetamine Abuse , 2006, Pharmacotherapy.

[27]  M. Subhash,et al.  Alterations in monoamine levels in discrete regions of rat brain after chronic administration of carbamazepine , 1994, Neurochemical Research.

[28]  K. Fuxe,et al.  The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus , 1997, Neuroreport.

[29]  C. Kamei,et al.  Histaminergic mechanisms in amygdaloid-kindled seizures in rats , 1998, Epilepsy Research.

[30]  K. Fuxe,et al.  The Vigilance Promoting Drug Modafinil Increases Extracellular Glutamate Levels in the Medial Preoptic Area and the Posterior Hypothalamus of the Conscious Rat: Prevention by Local GABAA Receptor Blockade , 1999, Neuropsychopharmacology.

[31]  E. Mignot,et al.  Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders , 2002, Nature Neuroscience.

[32]  S. Waller,et al.  Convulsive thresholds and severity and the anticonvulsant effect of phenobarbital and phenytoin in adult rats administered 6-hydroxydopamine or 5,7-dihydroxytryptamine during postnatal development , 1985, Pharmacology Biochemistry and Behavior.

[33]  P. Schwartzkroin,et al.  Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. , 2001, Brain research. Developmental brain research.

[34]  T. Spencer,et al.  Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro , 2006, Journal of Pharmacology and Experimental Therapeutics.

[35]  L. Goodman,et al.  Comparative assays of antiepileptic drugs in mice and rats. , 1952, The Journal of pharmacology and experimental therapeutics.

[36]  M Velasco,et al.  Acute and chronic electrical stimulation of the centromedian thalamic nucleus: modulation of reticulo-cortical systems and predictor factors for generalized seizure control. , 2000, Archives of medical research.

[37]  C. Kamei,et al.  Mechanism responsible for epileptogenic activity by first-generation H1-antagonists in rats , 2000, Brain Research.

[38]  K. Fuxe,et al.  The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission , 1998, Neuroscience Letters.

[39]  R. Bellazzi,et al.  The relationship between focal seizures and sleep: An analysis of the cyclic alternating pattern , 2005, Epilepsy Research.

[40]  D. Quartermain,et al.  Role of brain α1B‐adrenoceptors in modafinil‐induced behavioral activity , 2002, Synapse.

[41]  M. Subhash,et al.  Sodium valproate induced alterations in monoamine levels in different regions of the rat brain , 1994, Neurochemistry International.

[42]  M. Ding,et al.  Carnosine, a precursor of histidine, ameliorates pentylenetetrazole-induced kindled seizures in rat , 2006, Neuroscience Letters.

[43]  Takehiko Watanabe,et al.  Centrally acting histamine H1 antagonists promote the development of amygdala kindling in rats , 1996, Neuroscience Letters.

[44]  M. Sammaritano,et al.  Circadian rhythm, sleep, and epilepsy. , 1996, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[45]  C. Saper,et al.  Hypothalamic Arousal Regions Are Activated during Modafinil-Induced Wakefulness , 2000, The Journal of Neuroscience.

[46]  J. Wisor,et al.  Dopaminergic—adrenergic interactions in the wake promoting mechanism of modafinil , 2005, Neuroscience.

[47]  K. Saitou,et al.  The mechanism responsible for the drowsiness caused by first generation H1 antagonists on the EEG pattern. , 2000, Methods and findings in experimental and clinical pharmacology.

[48]  M. Subhash,et al.  Effect of chronic administration of phenytoin on regional monoamine levels in rat brain , 1995, Neurochemical Research.

[49]  C. Stafstrom.  Epilepsy: A Review of Selected Clinical Syndromes and Advances in Basic Science , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[50]  H. Ohtsu,et al.  Chemical kindling induced by pentylenetetrazol in histamine H1 receptor gene knockout mice (H1KO), histidine decarboxylase-deficient mice (HDC−/−) and mast cell-deficient W/Wv mice , 2003, Brain Research.

[51]  Christian Guilleminault,et al.  Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy , 2000, Neurology.