Modafinil is an increasingly popular
wake-promoting drug used for the treatment of
narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which
modafinil acts, we administered a range of doses of
modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast
modafinil-induced wakefulness with spontaneous wakefulness, we administered
modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected
modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg
modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in
orexin (
hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of
modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies,
modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that
modafinil may promote waking via activation of TMN and
orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.