Action of modafinil through histaminergic and orexinergic neurons

Modafinil is a wake-promoting drug used for the treatment of excessive daytime sleepiness due to narcolepsy as well as excessive sleepiness associated with obstructive sleep apnea and shift work disorder. Although the wake-promoting effect of modafinil is expressed through the dopaminergic and the norepinephrinergic systems similar to that of classical psychostimulants, the mechanism of action is distinct from those compounds in terms of the involvement of the histaminergic and the orexinergic systems. Modafinil activates the histaminergic system in an indirect manner, presumably via attenuation of the inhibitory GABAergic input to the histaminergic neurons. The orexinergic system controls arousal through the histaminergic system, and the modafinil-induced increment of histamine release is abolished in orexin neuron-ablated mice, suggesting that modafinil increases histaminergic tone via orexinergic neurons. Clinical and experimental investigations have suggested less importance of the orexinergic system in the wake-promoting effect of modafinil, but the orexinergic system is considered to be involved in modafinil-induced alertness or synaptic plasticity.