title: Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action.
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.
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, United States.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Mitchell
authors.forename: James W
authors.initials: JW
authors.lastname: Bogenpohl
authors.forename: L Cameron
authors.initials: LC
authors.lastname: Liles
authors.forename: Michael P
authors.initials: MP
authors.lastname: Epstein
authors.forename: Donna
authors.initials: D
authors.lastname: Bozyczko-Coyne
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D004299:Dopamine beta-Hydroxylase / Q000235:genetics* / Q000502:physiology*; D005475:Flupenthixol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000502:physiology*; D011224:Prazosin / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D004299:Dopamine beta-Hydroxylase; D005475:Flupenthixol; D000077408:Modafinil; D004298:Dopamine; D009638:Norepinephrine; D011224:Prazosin