A common thread in the mechanism of action of many sleep pharmacotherapies is NE. A pictorial representation integrating and summarizing the anatomical connections between noradrenergic neurons and the wake- and sleep-promoting systems, as well as potential sites of action of wake- and sleep-promoting drugs, is depicted in Fig. 1. For example, amphetamine directly induces release and blocks reuptake of NE, increasing its extracellular concentration and activating the ascending arousal pathway. And though the mechanism of modafinil has not been determined conclusively yet, its actions are blocked by α1AR antagonists, and there is some evidence that it may act as a NET inhibitor. In contrast, caffeine is one wake-promoting agent that does not appear to have a significant adrenergic component. On the other end of the sleep/wake spectrum, both benzodiazepines and z-drugs act to increase GABA transmission, resulting in inhibition of excitatory signals along arousal pathways, including those from the LC. NE is also involved in the synthesis of melatonin, and thus may help regulate the circadian as well as the homeostatic sleep processes. Finally, most antidepressants, including those used as insomnia treatments, affect the adrenergic system.