Behavioral responses of dopamine β-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 β-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 α1-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.

Behavioral and biochemical dissociation of arousal and homeostatic sleep need influenced by prior wakeful experience in mice

“…Dopamine antagonists inhibit the sleep latency increase caused by cage changes (23). Similarly, dopamine D2 receptor knockout mice do not exhibit longer sleep latencies after exposure to new environments (23,24). Furthermore, mice with histamine deficiency also fail to exhibit prolonged sleep latencies during CC manipulation (25).…”

Drug-induced sleep: theoretical and practical considerations

“…Modafinil shows activity at multiple sites, including evidence for a weak blockade of transporters of norepinephrine (NET) and dopamine (DAT) [36]. Although some antagonist studies have suggested the relatively greater importance of DAT [116], other studies suggest that noradrenergic stimulation of dopaminergic neurons also makes NET blockade important to wake promotion by modafinil [63]. Both D1 and D2 receptors are involved in the wake-promoting effect of modafinil [78], and a recent PET study using ( 11 C)raclopride and ( 11 C)cocaine showed that modafinil can block dopamine transporters and elevate dopamine levels in the human brain [107].…”

Armodafinil in the treatment of excessive sleepiness

“…58,59 Pharmacodynamics The modes of action of armodafinil and modafinil are currently not fully understood, although it is likely that they involve selective effects on catecholaminergic signaling in the central nervous system via dopaminergic, noradrenergic, and serotonergic receptors. [60][61][62] These effects are not well defined and despite ex-vivo assays showing binding of modafinil to the dopamine transporter and inhibition of dopamine reuptake, modafinil is not a direct or an indirect dopamine receptor agonist. 63 Hypocretin (or orexin)-producing neurons within the hypothalamus (postulated as preventing inappropriate changes in consciousness) are believed to be activated by modafinil to release dopamine and norepinephrine to promote wakefulness, 64 and this activity may also account for the observed clinical effect of armodafinil.…”

“…63 Hypocretin (or orexin)-producing neurons within the hypothalamus (postulated as preventing inappropriate changes in consciousness) are believed to be activated by modafinil to release dopamine and norepinephrine to promote wakefulness, 64 and this activity may also account for the observed clinical effect of armodafinil. 61,62 Furthermore, modafinil may potentiate wakefulness by increasing electrical coupling at gap junctions between neurons. 65 …”