Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic–dopaminergic mechanism of action
Open accessAbstract
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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Modafinil activates central, wake-promoting dopaminergic and noradrenergic mechanisms.
“Modafanil activates central, wake-promoting dopaminergic and noradrenergic mechanisms (25,26)”
From Sleep Restriction for 1 Week Reduces Insulin Sensitivity in Healthy Men (2010) · cites this paper as [26]
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Sleep Restriction for 1 Week Reduces Insulin Sensitivity in Healthy Men
Buxton, O. M., Pavlova, M., Reid, E. W., Wang, W., Simonson, D. C., & Adler, G. K. (2010) · Diabetes · doi:10.2337/db09-0699 · Cited by 604 · see citing works
“Modafanil activates central, wake-promoting dopaminergic and noradrenergic mechanisms (25;26) and ameliorates the adverse effects of sleep deprivation on alertness and performance (27-29), impairments in which have been attributed to reduced brain glucose utilization (30).”
Background
- 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)
- PMC
- PMC2597705
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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