Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Carmen Mazzola; Julie Medalie; Maria Scherma; Leigh V. Panlilio; Marcello Solinas; Gianluigi Tanda; Filippo Drago; Jean Lud Cadet; Steven R. Goldberg; Sevil Yasar

doi:10.1101/lm.1145209

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

¹Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA;
²Department of Experimental and Clinical Pharmacology, Medical School, University of Catania, Catania 86022, Italy;
³Department Laboratoire de Biologie et Physiologie Cellulaires, CNRS-6187, Université de Poitiers, 86022 Poitiers, France;
⁴Psychobiology Section, Medications Discovery Research Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA;
⁵Molecular Neuropsychiatry Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA;
⁶Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA

Abstract

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB₁-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for α-type peroxisome proliferator-activated nuclear receptors, PPAR-α) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-α agonist WY14643, and these enhancements were blocked by the PPAR-α antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-α, either directly by administering a PPAR-α agonist or indirectly by administering a FAAH inhibitor.