Scientific Report 2006

Molecular Biology

Hypocretins in Arousal, Feeding Behavior, and Motivation

J.G. Sutcliffe, L. de Lecea

The 2 C terminally amidated hypocretin neuropeptides (also called orexins) are produced from a precursor whose expression in rats is restricted to a few thousand neurons of the lateral hypothalamus. These neurons are active during wakefulness but are quiescent during various phases of sleep. Two G protein–coupled hypocretin receptors have different distributions within the CNS.

The hypocretins are found in secretory vesicles at synapses of fibers that project to areas within the posterior part of the hypothalamus that are implicated in feeding behaviors and hormone secretion. Hypocretin fibers also project to diverse targets in other brain regions and the spinal cord, including several areas implicated in cardiovascular function and sleep-wake regulation. The peptides are excitatory when applied directly in vivo. Most humans with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebral spinal fluid and no or barely detectable hypocretin neurons in their hypothalami, findings suggestive of autoimmune attack.

Hypocretin peptides excite noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe to elevate muscle tone and histaminergic tuberomammillary neurons to promote wakefulness.

These components of the ascending reticular activating system, and the hypocretin neurons themselves, project to and stimulate thalamic and basal forebrain neurons, and all of these groups contribute to the depolarization of the cerebral cortex. Arousal-related signaling occurs through both hypocretin receptors.

These peptides have diverse effects on brain reward and autonomic systems related to stress that increase motivated behaviors, including feeding. The relation to feeding is complex. Acute administration of hypocretin peptides to sleeping rats increases food consumption. However, patients and animals with impaired hypocretin signaling have an increased likelihood of being obese despite reduced daily calorie intake.

Publications

de Lecea L., Sutcliffe, J.G. The hypocretins and sleep. FEBS J. 272:5675, 2005.

Desplats, P.A., Kass, K.E., Gilmartin, T., Stanwood, G.D., Woodward, E.L., Head, S.R., Sutcliffe, J.G., Thomas, E.A. Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease. J. Neurochem. 96:743, 2006.

Hedlund, P.B., Huitrón-Reséndiz, S., Henriksen, S.J., Sutcliffe, J.G. 5-HT₇ receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol. Psychiatry 58:831, 2005.

Hedlund, P.B., Sutcliffe, J.G. 5-HT₇ receptors as favorable pharmacological targets for drug discovery. In: The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics. Roth, B.L. (Ed.). Humana Press, Totowa, NJ, 2006, p. 517.

Hilbush, B.S., Morrison, J.H., Young, W.G., Sutcliffe, J.G., Bloom, F.E. New prospects and strategies for drug target discovery in neurodegenerative disorders. NeuroRx 2:627, 2005.

Sutcliffe, J.G. de Lecea, L. The hypocretin/orexin system. In: Handbook of Contemporary Neuropharmacology. Sibley, D.R., et al. (Eds.). Wiley-InterScience, Hoboken, NJ, in press.

Sutcliffe, J.G., de Lecea, L. Hypocretins/orexins in brain function. In: Handbook of Neurochemistry and Molecular Neurobiology: Neuroactive Proteins and Peptides, 3rd ed. Lim, R. (Volume Ed.), Lajtha, A. (Series Ed.). Springer, New York, 2006, p. 499.