The neuropeptide orexin (also known as hypocretin) is hypothesized to play a critical role in the regulation of sleep-wake behavior. Lack of orexin produces narcolepsy, which is characterized by poor maintenance of wakefulness and intrusions of rapid eye movement (REM) sleep or REM sleep-like phenomena into wakefulness. Orexin neurons heavily innervate many aminergic nuclei that promote wakefulness and inhibit REM sleep. We hypothesized that orexin neurons should be relatively active during wakefulness and inactive during sleep. To determine the pattern of activity of orexin neurons, we recorded sleep-wake behavior, body temperature, and locomotor activity under various conditions and used double-label immunohistochemistry to measure the expression of Fos in orexin neurons of the perifornical region. In rats maintained on a 12 hr light/ dark cycle, more orexin neurons had Fos immunoreactive nuclei during the night period; in animals housed in constant darkness, this activation still occurred during the subjective night. Sleep deprivation or treatment with methamphetamine also increased Fos expression in orexin neurons. In each of these experiments, Fos expression in orexin neurons correlated positively with the amount of wakefulness and correlated negatively with the amounts of non-REM and REM sleep during the preceding 2 hr. In combination with previous work, these results suggest that activation of orexin neurons may contribute to the promotion or maintenance of wakefulness. Conversely, relative inactivity of orexin neurons may allow the expression of sleep. Key words: orexin; hypocretin; Fos; wake; wakefulness; sleep; REM; lateral hypothalamus; perifornical region; hypothalamus; thermoregulation; ratThe neuropeptide orexin (also known as hypocretin) is hypothesized to play a critical role in the regulation of wakefulness and sleep. Orexin is synthesized in neurons of the perifornical region and lateral hypothalamic area, and orexin fibers innervate brain regions known to regulate behavioral state such as the raphe nuclei, the locus coeruleus, the tuberomammillary nucleus, and the cholinergic neurons of the basal forebrain and pons (Peyron et al., 1998;Chemelli et al., 1999;Date et al., 1999). Orexin increases the firing rate of postsynaptic neurons via OX1 and OX2 receptors (Sakurai et al., 1998;Hagan et al., 1999). Recent observations demonstrate that impaired orexin transmission may result in narcolepsy, which is characterized by poor maintenance of wakefulness and intrusions of rapid eye movement (REM) sleep or REM sleep-like phenomena into wakefulness (for review, see Siegel, 1999). The brains of narcoleptics exhibit a nearly complete loss of neurons expressing orexin mRNA or peptide (Peyron et al., 2000;Thannickal et al., 2000), and individuals with narcolepsy often have unmeasurably low orexin levels in CSF . Canine narcolepsy is caused by mutations of the OX2 receptor (Lin et al., 1999), and orexin knock-out mice have a phenotype very similar to canine and human narcolepsy (Chemelli et al., 1999). Addi...

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.

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