Wake-Promoting Agents; Insights into Clinical Use and Molecular Perspectives

Wake-Promoting Agents (WPAs) such as amphetamine-like stimulants or modafinil, armodafinil, methyl phenidate, caffeine and nicotine reinforce the level of vigilance through an stimulated release of neurotransmitters implicated in the arousal threshold maintenance, hence shift the drive from the sleep-promoting to  wake-promoting system. The modulatory effects of WPAs on cortical activation pathways give rise to enhanced vigilance. For example, cholinergic neurons of the basal forebrain and the adenosine receptors on these neurons are agonized and antagonized by nicotine and caffeine, respectively. Caffeine similarly antagonizes adenosine receptors on the GABAergic neurons and intensifies the inhibitory drive in preoptic/anterior hypothalamus which involve in sleep induction. Modafinil however exerts its wake-promoting effects through stimulating the tuberomammillary nucleus and the hypocretinergic neurons which activate the ascending reticular activating system. Although many neutransmitter systems such as dopamine are thought to be involved upon the effects of WPAs, the empirical evidence to explain the exact mechanisms need to gain strength.