IN VIVO INHIBITION STUDIES OF FAAH

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Fatty acid amide hydrolase (FAAH) is the enzyme predominantly responsible for the catabolism of several fatty acid amides (FAA), including the endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide), the sleep-inducing agent oleamide, the food-suppressing compound N-oleoylethanolamine (OEA), and the peripheral pain-suppressing agent N-palmitoylethanolamine (PEA). The creation of genetically engineered mice that lack FAAH [ FAAH(-/-) mice] has provided a powerful model to evaluate the function of this enzyme. These mice exhibit a CBl-mediated reduction in pain sensitivity, accompanied by substantial increases in endogenous anandamide levels in the CNS and periphery compared to wild type mice. In the studies proposed in this application (Project III), we will evaluate the in vivo effects of a series of highly selective and reversible FAAH inhibitors. These FAAH inhibitors provide complementary tools to further our understanding of the physiological functions of the FAAH/FAA system. Specifically, we will focus on the following goals: 1) identify selective, efficacious, potent, reversible FAAH inhibitors suitable for in vivo analysis; 2) characterize selected FAAH inhibitors and FAAH mutant mice in behavioral assays for pain, cognition, emotional behavior, and drug dependence; 3) correlate changes of anandamide and other FAAs in CNS areas associated with the behavioral changes; and 4) elucidate molecular mechanisms of action for FAAH inhibitors. While this Project is focused on investigating the function of FAAH in whole animals, these studies will be tightly linked to studies described in Projects I and II of the Program Project, in which the structural, biochemical, and cellular characterization of FAAH will be used to design highly selective inhibitors of this enzyme and create mutant mice that express FAAH variants with altered functional properties. Implications of this work should not only increase our understanding of the role that the FAAH-FAA system plays in a variety of neurobehavioral processes, but also may lead to the development of a new class of therapeutic drugs for the treatment of pain, anxiety, and substance abuse.