Introduction Natural Lipids Have Recently Been Proposed to Be Involved in the Regulation of Physiologic Functions in the Central Nervous

NATURAL LIPIDS HAVE RECENTLY BEEN PROPOSED TO BE INVOLVED IN THE REGULATION OF PHYSIOLOGIC FUNCTIONS IN THE CENTRAL NERVOUS SYSTEM. For example, N-arachidonoyl ethanolamine (anandamide), an endogenous ligand for cannabinoids receptors, induces hypothermia, analgesia, sleep, and locomotor and memory deficits in vivo.1-4 Whereas 9-(Z)-octadecenamide (oleamide) promotes sleep, hypothermia, and alterations in motor activity in rodents.57 Both anandamide and oleamide are members of the same class of endogenous lipids, the fatty acid amides (FAAs),8 and are rapidly hydrolyzed, in vivo, by a brain membrane-bound enzyme, fatty acid amide hydrolase (FAAH).9-13 Since its identification, FAAH has been cloned in numerous organs in mouse, rats, and humans, revealing a high degree of homology in its amino-acid sequence with a comparable affinity for its target substrates.9,10,14 In the brain, FAAH is localized to pyramidal cortical neurons, hippocampal pyramidal cells, mitral cells in olfactory bulb, cerebellar Purkinje neurons, and the choroid plexus, while lowest concentrations have been detected in brainstem regions and the hypothalamus.15-18 Selective FAAH inhibitors have been developed in an effort to study, in detail, the chemical characteristics and sites of action of FAAs.19-20 However, such studies have predominantly utilized in vitro preparations, whereas the in vivo properties of FAAH inhibitors are only beginning to be investigated.21 In an attempt to study the role that FAAH plays in regulating FAAs levels and activity, in vivo, a mouse-model that possesses a target disruption of the FAAH gene [FAAH (-/-)] was generated.22 FAAH (-/-) mice possess a 15-fold increase in brain levels of anandamide compared to normal mice, whereas the administration of anandamide or oleamide in FAAH (-/-) mice induces similar, but highly intensified behavioral responses, including hypomotility, analgesia, and hypothermia,22,23 to those elicited by these FAAs in wild type rodents.1,7 The fact that FAAH (-/-) mice showed an increase in endogenous levels of anandamide,22 as well as reduced hydrolytic rates for anandamide and oleamide,23 raises a question concerning the sleep-wake cycle of these mice. Herein, we characterized the patterns of sleep and wakefulness in FAAH (-/-) mice that exhibited a significant increase in the amount of slow-wave sleep (SWS) during their rest phase compared to their heterozygote [FAAH (+/-)] and normal [FAAH (+/+)] littermates. In addition, because sleep deprivation is an experimental procedure for studying sleep homeostasis, we sleep deprived FAAH (-/-), (+/+), and (+/-) mice during 8 hours to investigate the role of FAAs in the homeostatic regulation of sleep on these mice.