Cited by 51Neurotransmitter Receptor Influence on BehaviorSleep and Wakefulness ResearchSleep and Work-Related Fatigue

Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic–dopaminergic mechanism of action

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Mitchell, Heather A., Bogenpohl, James W., Liles, L. Cameron, Epstein, Michael P., Bozyczko-Coyne, Donna, Williams, Michael, Weinshenker, David·2008·Pharmacology Biochemistry and Behavior

Abstract

Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine beta-hydroxylase knockout (Dbh -/-) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh -/- mice completely lack NE but have hypersensitive DA signaling. It was hypothesized that Dbh -/- mice would be unresponsive to modafinil if the compound acts primarily via NE, but would be hypersensitive to modafinil if it acts primarily via DA. Dbh -/- mice had increased sensitivity to the locomotor-activating and wake-promoting effects of modafinil. Paradoxically, the alpha1-adrenergic receptor antagonist, prazosin, attenuated the effects of modafinil in control mice, but not in Dbh -/- mice. Blockade of DA receptors with flupenthixol decreased modafinil-induced locomotion and wake in both control and Dbh -/- mice. These results suggest that both NE and DA are involved in the behavioral effects of modafinil in control mice, but the requirement for NE can be bypassed by hypersensitive DA signaling.

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Crossref · 10.1016/j.pbb.2008.07.014

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Authors
Mitchell, H. A., Bogenpohl, J. W., Liles, L. C., Epstein, M. P., Bozyczko-Coyne, D., Williams, M., & Weinshenker, D.
Affiliations
Emory University (US)
Corresponding author
Weinshenker, David
Venue
Pharmacology Biochemistry and Behavior
Publisher
Elsevier BV
Published
2008-12
Volume
91
Issue
2
Pages
217-222
ISSN
0091-3057 (ISSN-L)
OpenAlex
W2068249288
Cited by
51
References
51
Citations by year
2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2020: 2 · 2019: 4 · 2018: 3 · 2016: 2 · 2013: 6 · 2012: 8
FWCI
2.45
Type
journal article
Language
en
Open access
Locations
  • Pharmacology Biochemistry and Behavior (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Drug Abuse (DA017963, R01DA017963)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
Keywords
modafinil, norepinephrine, dopamine, arousal, wakefulness, excessive daytime sleepiness, locomotor activation, sleep latency, prazosin, flupenthixol, alpha1-adrenoceptors
MeSH terms
Modafinil, Adrenergic alpha-Antagonists, Central Nervous System Stimulants, Animals, Behavior, Animal, Benzhydryl Compounds, Dopamine, Dopamine beta-Hydroxylase, Flupenthixol, Mice, Inbred C57BL, Motor Activity, Norepinephrine, Prazosin, Receptors, Adrenergic, Receptors, Dopamine, Sleep, Wakefulness, Mice, Knockout, Dopamine Antagonists, Dopamine Plasma Membrane Transport Proteins, Mice, Adrenergic alpha-1 Receptor Antagonists

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