Elsevier

Neuroscience Letters

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

Modanifil activates the histaminergic system through the orexinergic neurons

https://doi.org/10.1016/j.neulet.2010.08.005Get 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.

References (31)

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    Citation Excerpt :

    Beyond dopaminergic effects, both modafinil and METH interact with norepinephrine (NE) and histamine systems as part of their respective pharmacokinetics (Munzar et al., 2004; Ishizuka et al., 2010; Ferrucci et al., 2013; Wisor, 2013). Additionally, modafinil and METH have been shown to activate orexinergic neurons, which induces wakefulness by stimulation DA, NE and histamine neurotransmission (Estabrooke et al., 2001; Ishizuka et al., 2010; Mahler et al., 2012). Glutamatergic neurotransmission in the corticostriatal pathway is essential for motivated behaviors and it is well known that psychostimulant intake may alter synaptic plasticity (Kauer and Malenka, 2007; Parsegian and See, 2014; González et al., 2016).

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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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