Disharmony between wake- and respiration-promoting activities: effects of modafinil on ventilatory control in rodents

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Abstract

Background

Modafinil is a wake-promoting drug and has been widely used for daytime sleepiness in patients with narcolepsy and other sleep disorders. A recent case series reported that daily oral modafinil alleviated hypercapnic respiratory failure in patients with COPD. However, the precise action of modafinil on respiration such as hypercapnic and/or hypoxic ventilatory responses remains unclear. The aim of this study is to clarify the effect of modafinil on the ventilatory control.

Methods

We investigated the hypothesis that modafinil enhances resting ventilation as well as the stimulatory ventilatory responses to hypercapnia and hypoxia. We addressed the issue by examining minute ventilation, respiratory rate and volume components using plethysmography, combined with a concurrent EEG monitoring of the level of wakefulness before and after administration of modafinil in two doses of 100 mg/kg and 200 mg/kg in unanesthetized mice. In addition, we monitored the effect of the lower dose of modafinil on mice locomotor activity in a freely moving condition by video-recording.

Results

Wakefulness, locomotor activity and variability of the breathing pattern in tidal volume were promoted by both doses of modafinil. Neither dose of modafinil increased the absolute values of resting ventilation or promoted the ventilatory responses to hypercapnia and hypoxia. Rather, higher dose of modafinil slightly suppressed respiratory rate in room air condition.

Conclusions

Modafinil is conducive to the state of wakefulness but does not augment resting ventilation or the hyperventilatory responses to chemical stimuli in unanesthetized rodents.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-016-0466-9) contains supplementary material, which is available to authorized users.

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Most cited references 34

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Breathing: rhythmicity, plasticity, chemosensitivity.

Jack Feldman, Gordon Mitchell, Eugene E Nattie (2003)

Breathing is a vital behavior that is particularly amenable to experimental investigation. We review recent progress on three problems of broad interest. (i) Where and how is respiratory rhythm generated? The preBötzinger Complex is a critical site, whereas pacemaker neurons may not be essential. The possibility that coupled oscillators are involved is considered. (ii) What are the mechanisms that underlie the plasticity necessary for adaptive changes in breathing? Serotonin-dependent long-term facilitation following intermittent hypoxia is an important example of such plasticity, and a model that can account for this adaptive behavior is discussed. (iii) Where and how are the regulated variables CO2 and pH sensed? These sensors are essential if breathing is to be appropriate for metabolism. Neurons with appropriate chemosensitivity are spread throughout the brainstem; their individual properties and collective role are just beginning to be understood.

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Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review.

R Battleday, A-K Brem (2015)

Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin, and histamine levels, and indirectly decreases cerebral gamma-amino-butrytic acid levels. In addition to its approved use treating excessive somnolence, modafinil is thought to be used widely off-prescription for cognitive enhancement. However, despite this popularity, there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy, non-sleep-deprived humans. This problem is compounded by methodological discrepancies within the literature, and reliance on psychometric tests designed to detect cognitive effects in ill rather than healthy populations. In order to provide an up-to-date systematic evaluation that addresses these concerns, we searched MEDLINE with the terms "modafinil" and "cognitive", and reviewed all resultant primary studies in English from January 1990 until December 2014 investigating the cognitive actions of modafinil in healthy non-sleep-deprived humans. We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes. Finally, in light of the methodological discrepancies encountered within this literature, we conclude with a series of recommendations on how to optimally detect valid, robust, and consistent effects in healthy populations that should aid future assessment of neuroenhancement.

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Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil.

Wei-Min Qu, Zhi-Li Huang, Xin-Hong Xu … (2008)

Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases wakefulness is debated. Herein we used dopamine (DA) D(2) receptor (D(2)R)-deficient mice combined with D(1)R- and D(2)R-specific antagonists to clarify the role of DA receptors in the arousal effects of modafinil. In wild-type mice, intraperitoneal modafinil induced wakefulness in a dose-dependent manner. Pretreatment with either D(1)R antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] at 30 microg/kg or D(2)R antagonist raclopride at 2 mg/kg blocked the arousal effects of low-dose modafinil at 22.5 and 45 mg/kg. When modafinil was given at 90 and 180 mg/kg, pretreatment of D(1)R antagonist did not affect the wakefulness at all, whereas D(2)R antagonist significantly attenuated the wakefulness to the half level compared with vehicle control. Similarly, D(2)R knock-out (KO) mice exhibited attenuated modafinil-induced wakefulness. However, pretreatment of D(2)R KO mice with D(1)R antagonist completely abolished arousal effects of modafinil. These findings strongly indicate that dopaminergic D(1)R and D(2)R are essential for the wakefulness induced by modafinil.

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Author and article information

Contributors

Jiro Terada: +81-43-222-7171 , jirotera@chiba-u.jp

Isato Fukushi: isato16@pc4.so-net.ne.jp

Kotaro Takeda: ktakeda@fujita-hu.ac.jp

Yohei Hasebe: yoheihasebe@icloud.com

Mieczyslaw Pokorski: m_pokorski@hotmail.com

Koichiro Tatsumi: tatsumi@faculty.chiba-u.jp

Yasumasa Okada: yasumasaokada@1979.jukuin.keio.ac.jp

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 14 November 2016

Publication date PMC-release: 14 November 2016

Publication date (Print): 2016

Volume: 17

Electronic Location Identifier: 148

Affiliations

[1 ]Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba city, Chiba 260-8670 Japan

[2 ]Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011 Japan

[3 ]Department of Biomedical Engineering, Graduate School of Science and Engineering, Toyo University, 2100 Kujirai, Kawagoe, Saitama 350-8585 Japan

[4 ]Fujita Memorial Nanakuri Institute, Fujita Health University, 423 Oodori-cho, Tsu, Mie 514-1296 Japan

[5 ]Department of Pediatrics, School of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898 Japan

[6 ]Opole Medical School, 68 Katowicka Street, Opole, 45-060 Poland

Article

Publisher ID: 466

DOI: 10.1186/s12931-016-0466-9

PMC ID: 5109771

PubMed ID: 27842553

SO-VID: 43de1a9b-fa52-4e47-b3d2-2da3a883d9a9

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 July 2016

Date accepted : 2 November 2016

Funding

Funded by: KAKENHI, Grant Numbers, 25540130, 26460311, 26670676 and 15K00417

Funded by: KAKENHI, Grant Number 24790803

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: breathing,electroencephalogram,hypercapnic ventilatory response,hypoxic ventilatory response,narcolepsy,respiratory failure,vigilance,wake-promoting drug

Data availability:

ScienceOpen disciplines: Respiratory medicine

Keywords: breathing, electroencephalogram, hypercapnic ventilatory response, hypoxic ventilatory response, narcolepsy, respiratory failure, vigilance, wake-promoting drug

Disharmony between wake- and respiration-promoting activities: effects of modafinil on ventilatory control in rodents

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Inflamed lung in vitro co-culture models

Most cited references 34

Breathing: rhythmicity, plasticity, chemosensitivity.

Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review.

Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil.

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