Adrenergic Signaling Plays a Critical Role in the Maintenance of Waking and in the Regulation of REM Sleep

• Published in: Journal of neurophysiology Vol. 92; no. 4; pp. 2071 - 2082
• Main Authors: Ouyang, Ming, Hellman, Kevin, Abel, Ted, Thomas, Steven A
• Format: Journal Article
• Language: English
• Published: United States Am Phys Soc 01.10.2004
• Subjects: Adrenergic alpha-Agonists - pharmacology; Animals; Dopamine beta-Hydroxylase - genetics; Dopamine beta-Hydroxylase - physiology; Electroencephalography; Electromyography; Epinephrine - pharmacology; Female; Genotype; Homeostasis - physiology; Male; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Motor Activity - physiology; Norepinephrine - pharmacology; Phenotype; Receptors, Adrenergic, alpha-1 - physiology; Sleep Deprivation - physiopathology; Sleep, REM - physiology; Sympathetic Nervous System - physiology; Wakefulness - physiology
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00226.2004

Departments of 1 Pharmacology and 2 Biology and 3 Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084 Submitted 5 March 2004; accepted in final form 3 June 2004 Many experiments have suggested that the adrenergic system is important for arousal and the regulation of sleep/wake states. Electrophysiological studies have found strong correlations between the firing of adrenergic neurons and arousal state. Lesions of adrenergic neurons have been reported to cause changes in sleep/wake regulation, although findings have been variable and sometimes transient. To more specifically address the role of adrenergic signaling in sleep/wake regulation, we performed electroencephalographic and electromyographic recordings in mice with a targeted disruption of the gene for dopamine -hydroxylase, the enzyme that converts dopamine to norepinephrine. These mice are unable to synthesize the endogenous adrenergic ligands norepinephrine and epinephrine. The mutant mice sleep 2 h more each day. The decrease in waking is due to a considerable decrease in the duration of waking bouts in spite of an increase in the number of waking bouts and transitions from sleep to waking. In contrast, the amount of rapid-eye-movement (REM) sleep is only half that in control mice due to a decrease in the number and duration of REM sleep bouts. Delta power is selectively increased in the mutant mice, and there is much less variation in non-REM sleep delta power over 24 h. After 6 h of total sleep deprivation during the first half of the light period, there is no rebound recovery of sleep time in the mutant mice. These results provide genetic evidence that adrenergic signaling acts to maintain waking and is important for the regulation of REM sleep and possibly sleep homeostasis. Address for reprint requests and other correspondence: S. A. Thomas, Dept. of Pharmacology, University of Pennsylvania, 103 John Morgan Bldg., 3620 Hamilton Walk, Philadelphia, PA 19104-6084 (E-mail: thomas{at}pharm.med.upenn.edu ).