Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice
by
Michihiro Mieda *, Jon T. Willie *, Junko Hara , Christopher M. Sinton ¶, Takeshi Sakurai , and Masashi Yanagisawa *||
*Department of Molecular Genetics and Howard Hughes Medical Institute, and ¶Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan; and Exploratory Research for Advanced Technology, Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo 135-0064, Japan
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0400590101

ABSTRACT

Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that orexin neuron-ablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.

Orexin A
The sleep-switch
Modafinil: structure
Modafinil and serotonin
Modafinil and the aviator
Modafinil and the marmoset
Modafinil: pharmacokinetics
Modafinil as an antidepressant
Orexins and forebrain cholinergic neurons
Narcolepsy and Sleep Disorders: some hotlinks
Mood-lifting effect of caloric restriction is mediated by orexin

Refs
and further reading

HOME
HedWeb
Nootropics
cocaine.wiki
Future Opioids
BLTC Research
MDMA/Ecstasy
Superhapiness?
Utopian Surgery?
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
Critique of Huxley's Brave New World

The Good Drug Guide
The Responsible Parent's Guide
To Healthy Mood Boosters For All The Family