Narcolepsy-
cataplexy, a disorder of excessive
sleepiness and abnormalities of rapid eye movement (REM) sleep, results from deficiency of the hypothalamic
orexin (
hypocretin)
neuropeptides.
Modafinil, an atypical wakefulness-promoting agent with an unknown mechanism of action, is used to treat
hypersomnolence in these patients. Fos
protein immunohistochemistry has previously demonstrated that
orexin neurons are activated after
modafinil administration, and it has been hypothesized that the wakefulness-promoting properties of
modafinil might therefore be mediated by the
neuropeptide. Here we tested this hypothesis by immunohistochemical, electroencephalographic, and behavioral methods using
modafinil at doses of 0, 10, 30 and 100 mg/kg i.p. in
orexin-/- mice and their wild-type littermates. We found that
modafinil produced similar patterns of neuronal activation, as indicated by Fos immunohistochemistry, in both genotypes. Surprisingly,
modafinil more effectively increased wakefulness time in
orexin-/- mice than in the wild-type mice. This may reflect compensatory facilitation of components of central arousal in the absence of
orexin in the null mice. In contrast, the compound did not suppress direct transitions from wakefulness to REM sleep, a sign of
narcolepsy-
cataplexy in mice. Spectral analysis of the electroencephalogram in awake
orexin-/- mice under baseline conditions revealed reduced power in the theta; band frequencies (8-9 Hz), an index of alertness or attention during wakefulness in the rodent.
Modafinil administration only partly compensated for this attention deficit in the
orexin null mice. We conclude that the presence of
orexin is not required for the wakefulness-prolonging action of
modafinil, but
orexin may mediate some of the alerting effects of the compound.