Hypothalamic arousal regions are activated during modafinil-induced wakefulness

Modafinil is an increasingly popular wake-promoting drug used for the treat ment of narcolepsy, but its precise mechanism of action is unknown. To dete rmine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied th e pattern of neuronal activation using Fos immunohistochemistry. To contras t modafinil-induced wakefulness with spontaneous wakefulness, we administer ed modafinil at midnight, during the normal waking period of rats. To deter mine the influence of circadian phase or ambient light, we also injected mo dafinil at noon on a normal light/dark cycle or in constant darkness. We fo und that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomam millary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornica l area, two cell groups implicated in the regulation of wakefulness. This l ow dose of modafinil also increased the number of Fos-immunoreactive (Fos-I R) neurons in the lateral subdivision of the central nucleus of the amygdal a. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produc e statistically significant increases in Fos expression in either the supra chiasmatic nucleus or the anterior hypothalamic area. These observations su ggest that modafinil may promote waking via activation of TMN and orexin ne urons, two regions implicated in the promotion of normal wakefulness. Selec tive pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.