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The Journal of Neuroscience, October 15, 2000, 20(20):7760-7765

Hypocretin-1 Modulates Rapid Eye Movement Sleep through Activation of Locus Coeruleus Neurons

Patrice Bourgin¹, Salvador Huitrón-Reséndiz², Avron D. Spier¹, Véronique Fabre², Beatriz Morte¹, José R. Criado², J. Gregor Sutcliffe¹, Steven J. Henriksen², and Luis de Lecea^{1, 2}

Departments of ¹ Molecular Biology and ² Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

The hypocretins (hcrts), also known as orexins, are two recently identified excitatory neuropeptides that in rat are produced by ~1200 neurons whose cell bodies are located in the lateral hypothalamus. The hypocretins/orexins have been implicated in the regulation of rapid eye movement (REM) sleep and the pathophysiology of narcolepsy. In the present study, we investigated whether the locus coeruleus (LC), a structure receiving dense hcrtergic innervation, which is quiescent during REM sleep, might be a target for hcrt to regulate REM sleep. Local administration of hcrt1 but not hcrt2 in the LC suppressed REM sleep in a dose-dependent manner and increased wakefulness at the expense of deep, slow-wave sleep. These effects were blocked with an antibody that neutralizes hcrt binding to hcrt receptor 1. In situ hybridization and immunocytochemistry showed the presence of hcrt receptor 1 but not the presence of hcrt receptor 2 in the LC. Iontophoretic application of hcrt1 enhanced the firing rate of LC neurons in vivo, and local injection of hcrt1 into the LC induced the expression of c-fos in the LC area. We propose that hcrt receptor 1 in the LC is a key target for REM sleep regulation and might be involved in the pathophysiological mechanisms of narcolepsy.

Key words: norepinephrine; orexin; orexin receptors; c-fos; arousal; microinjection; immunocytochemistry

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20207760-06$05.00/0

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