Effect of Oleamide on Sleep and Its Relationship to Blood Pressure, Body Temperature, and Locomotor Activity in Rats Salvador Huitro ´n-Rese ´ndiz,* Lhys Gombart,* Benjamin F. Cravatt,† and Steven J. Henriksen* ,1 *Department of Neuropharmacology and †Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037 Received April 12, 2001; accepted July 16, 2001 Oleamide (cis-9,10-octadecenoamide) is a brain lipid that has recently been isolated from the cerebral fluid of sleep-deprived cats. Intracerebroventricular and intraperitoneal administration of oleamide induces sleep in rats. However, it is unclear whether oleam- ide’s hypnogenic effects are mediated, in part, by its actions on blood pressure and core body temperature. Here we show that systemic administration of oleam- ide (10 and 20 mg/kg) in rats increased slow-wave sleep 2, without affecting blood pressure and heart rate. In addition, oleamide decreased body temperature and locomotor activity in a dose-dependent manner. These latter effects were not correlated in time with the ob- served increases in slow-wave sleep. These data sug- gest that the hypnogenic effects of oleamide are not related to changes in blood pressure, heart rate, or body temperature. © 2001 Academic Press Key Words: oleamide; sleep; body temperature; mo- tor activity; blood pressure. INTRODUCTION Identifying endogenous sleep-promoting substances has reemerged in recent years and there is increasing evidence for a role of a variety of endogenous agents in regulating physiological sleep in mammals. Indeed, hormones, cytokines, lipids, and other peptides have been implicated in triggering sleep (see (24, 42)). Re- cently, we (30) reported that a novel brain lipid isolated from the cerebrospinal fluid of sleep-deprived cats was found to accumulate and disappear under conditions of sleep deprivation and recovery, respectively. The sub- stance was determined to be cis-9,10-octadecenoamide (oleamide) (Fig.1). Likewise, levels of oleamide in the cerebrospinal fluid (CSF) of sleep-deprived rats have been measured showing significant increments after 6 h of sleep deprivation (3). Oleamide and other alkane-chain fatty acid amides, including anandamide, the endogenous ligand for the cannabinoid receptor, constitute a novel group of ami- dated lipids that are normally found in the brain and blood of mammals, including humans (2, 7, 8, 30). Since its identification and isolation, oleamide has been involved in diverse cellular and physiological functions. In vitro, oleamide inhibits lymphocyte pro- liferation (26), potentiates the action of serotonin on some receptor subtypes (5-HT 2A , 5-HT 2C , and 5-HT 1A ) (4, 23, 43,), modulates 5-HT 7 receptor-mediated effects (44), blocks gap junction communication (5, 17), and potentiates GABA A receptors (28, 29, 45, 46). On the other hand, studies characterizing the in vivo effects of oleamide in rats have shown that this amide produces hypomotility (3) and hypothermia. (Henriksen, unpub- lished studies). Likewise, we observed (7) that intra- peritoneal (ip) and intracerebroventricular (icv) ad- ministration of oleamide induces sleep in rats, while other authors have reported that icv administration of oleamide only decreased sleep latency (3, 36). More- over, one study reported no differences in the amount of total sleep after administration of oleamide (12). It has been proposed that the hypnogenic properties of some putative sleep factors are related to changes in blood pressure (16). In view of the controversial effects of oleamide on sleep and the possibility that its effects could be mediated by disruptions in blood pressure (BP) and body temperature (Tb), we examined the ef- fects of oleamide (ip) on sleep, BP, heart rate (HR), and Tb in rats. METHODS Animals and surgery. Sixteen male Sprague–Daw- ley rats (300 –350 g) were implanted under halothane anesthesia (1–2%) with a standard set of stainless- steel screw electrodes for chronic sleep recordings. The electroencephalogram (EEG) was recorded from elec- trodes placed in the frontal and parietal bone over the hippocampus (P = 4.0; L = 3.0). A third EEG electrode was placed in the skull over the cerebellum and served to ground the animal to reduce signal artifacts. Two 1 To whom correspondence should be addressed at Department of Neuropharmacology (CVN-13), The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Fax: (858) 784- 7385. E-mail: steven@scripps.edu. Experimental Neurology 172, 235–243 (2001) doi:10.1006/exnr.2001.7792, available online at http://www.idealibrary.com on 235 0014-4886/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.