Modanifil activates the histaminergic system through the orexinergic neurons

doi:10.1016/j.neulet.2010.08.005

Neuroscience Letters

Volume 483, Issue 3, 15 October 2010, Pages 193-196

https://doi.org/10.1016/j.neulet.2010.08.005 Get rights and content

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.

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Acknowledgement

We are very grateful to Prof. Takeshi Sakurai (Department of Molecular Neuroscience and Integrative Physiology, Graduate School of Medical Science, Kanazawa University) for providing orexin neuron-deficient mice.

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Citation Excerpt :
Modafinil affects the P450 enzyme system, induces 1A2 and 3A, and inhibits 2C19. Therefore there will be drug interactions in patients taking contraceptive drugs, benzodiazepines, and drugs that are metabolized by the P450 system.11 This paper reports a case of an OSA sufferer who gives symptoms of excessive sleepiness during the day.
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This case presents a 39-year-old man complains of excessive sleepiness during the day for10 years with a duration of 10–15 min, often waking up at night and feeling tired all day. Overnight polysomnography showed Respiratory Disturbance Index 21.6. The patient received 6 cmH₂O of Continues Positive Airways Pressure (CPAP) therapy every night during sleep and modafinil 100 mg once a day.
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¹: Present address: Division of Neurology/Molecular Brain Science, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.

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Modanifil activates the histaminergic system through the orexinergic neurons

Abstract

Section snippets

Acknowledgement

Cell

Neuroscience

Neuron

Neurosci. Lett.

Behav. Brain Res.

Eur. J. Pharmacol.

Neurosci. Lett.

Neurosci. Lett.

Curr. Opin. Neurobiol.

Behav. Brain Res.

Lancet

Eur. J. Pharmacol.

Neuroscience

Brain Res.

Neuroscience