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COMPLEX FUNCTIONS OF THE CENTRAL NERVOUS SYSTEM, SLEEP AND LOCOMOTION

A cyclooxygenase-2 inhibitor attenuates spontaneous and TNF--induced non-rapid eye movement sleep in rabbits

Department of Veterinary, Comparative Anatomy, Pharmacology and Physiology, College of Veterinary Medicine, Washington State University, Pullman, Washington 99164-6520

Submitted 3 October 2002 ; accepted in final form 5 March 2003

Sleep is regulated in part by the brain cytokine network, including tumor necrosis factor- (TNF-). TNF- activates the transcription factor nuclear factor-B, which in turn promotes transcription of many genes, including cyclooxygenase-2 (COX-2). COX-2 is in the brain and is an enzyme responsible for production of prostaglandin D₂. The hypothesis that central COX-2 plays a role in the regulation of spontaneous and TNF--induced sleep was investigated. Three doses (0.5, 5, and 50 µg) of NS-398, a highly selective COX-2 inhibitor, were injected intracerebroventricularly. The highest dose decreased non-rapid eye movement sleep. The intermediate and highest doses decreased electroencephalographic slow-wave activity; the greatest reduction occurred after 50 µg of NS-398 during the first 3-h postinjection period. Rapid eye movement sleep and brain temperature were not altered by any dose of NS-398. Pretreatment of rabbits with 5 or 50 µg of NS-398 blocked the TNF--induced increases in non-rapid eye movement sleep, electroencephalographic slow-wave activity, and brain temperature. These data suggest that COX-2 is involved in the regulation of spontaneous and TNF--induced sleep.

electroencephalogram; cytokine; slow-wave activity

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