title: Modanifil activates the histaminergic system through the orexinergic neurons.
abstract: Modafinil is a drug used to treat hypersomnolence of narcolepsy. We previously reported that modafinil increases hypothalamic histamine release in rats but did not increase locomotor activity in histamine-depleted mice, suggesting that modafinil-induced locomotor activity involves the histaminergic system. Modafinil is also thought to express its effect through the orexinergic neurons, and orexin increases hypothalamic histamine release. These findings led us to investigate whether modafinil activates the histaminergic system via the orexinergic system. In the present study, we performed in vivo microdialysis and c-Fos immunohistochemistry to investigate whether the orexinergic system mediates the activation of the histaminergic system by modafinil using orexin neuron-deficient mice. Two hours after the injection, modafinil (150 mg/kg) caused a significant increase of histamine release compared to the basal release in wild type mice. However, modafinil had no effect on the histamine release in orexin neuron-deficient mice. By immunohistochemical study, we found that there was no neuronal activation in the tuberomammillary nucleus where the cell bodies of the histaminergic neurons exclusively exist in orexin neuron-deficient mice. These findings indicate that modafinil-induced increment of histamine release requires intact orexinergic neurons.
authors.affiliation: Department of Medical Science and Technology, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University, Japan. ishizuka@cc.osaka-dent.ac.jp
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Murotani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamatodani
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D006632:Histamine / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000077408:Modafinil; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000172:deficiency / Q000378:metabolism*; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D006632:Histamine; D000077408:Modafinil