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

Abstract

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB 1 -receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR-a) 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-a agonist WY14643, and these enhancements were blocked by the PPAR-a antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-a, either directly by administering a PPAR-a agonist or indirectly by administering a FAAH inhibitor.Peroxisome proliferator-activated receptor-a (PPAR-a) is a ligandactivated transcriptional factor that regulates the expression of genes involved in lipid utilization, fatty acid oxidation, and inflammation (van Raalte et al. 2004;LoVerme et al. 2006). Immunolocalization studies of PPAR-a in the adult rat brain suggest that this nuclear receptor might have specific functions in regulating expression of genes involved in cholinergic neurotransmission and learning and memory processes (Moreno et al. 2004;Cimini et al. 2005). For example, there are high concentrations of PPAR-a receptors in the hippocampus and amygdala (Moreno et al. 2004). However, the potential involvement of PPAR-a in learning and memory processes has not been systematically investigated.Endogenous ligands for PPAR-a include the lipid mediators N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). In addition, anandamide (N-arachidonoylethanolamine), which has primarily been studied as an endogenous ligand for G-proteincoupled cannabinoid CB 1 receptors that mediate the behavioral effects of cannabis and its active constituent D 9-tetrahydrocannabinol (THC) (Devane et al. 1992;Solinas et al. 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al. 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al. 2001;Fu et al. 2003) and PEA as an anti-inflammatory factor (Kuehl et al. 1957;Calignano et al. 1998;Jaggar et al. 1998). OEA and PEA are structurally similar to anandamide but do not bind to or activate cannabinoid CB 1 receptors. Anandamide, OEA, and PEA are all inactivated primarily by the intracellular serine enzyme, fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman 2002;Fegley et al. 2005). Consequently, selective FAAH-inhibiting drugs such as cyclohexyl carbamic acid 39-carbamoyl-3-yl ester (URB597) increase endogenous levels of anandamide, OEA, and PEA in the brain (Fegley et al. 2005;Piomelli et al. 2006).In the present experiments, the effects of FAAH inhibition on learning and memory processes and the involvement of cannabinoid CB 1 receptors and PPAR-a nuclear receptors in those effects were studied using a passive-avoidance procedure in rats. FAAH inhibition was accomplished by administering U...

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1and CB2

“…These effects were reduced after administration of rimonabant, SR144528, or MK886, dependent on the paradigm under study. In a passive avoidance paradigm, URB597 administration to rats 40 min before testing enhanced memory acquisition (Mazzola et al, 2009), whereas ⌬ 9 -THC administration impaired memory. The URB597 enhancement was reduced by either rimonabant or MK886.…”

The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body Weight

“…It is conceivable, then, that OEA mobilized in the gut after a fat-rich meal initiates an integrated response that prompts enhanced encoding of information about the spatial and emotional context in which the meal was consumed [130]. Synthetic PPARα agonists and inhibitor of FAAHs as well seem to ameliorate memory acquisition in a passive avoidance task in rats [131].…”

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

“…Mazzola et al 9 showed that memory acquisition in rats is enhanced by the FAAH inhibitor URB597, which was sensitive to PPARα antagonism. Campologno et al 20 showed that OEA administration also has a central memory enhancing effect which was absent in PPARα-null mice.…”

“…These tables do not include studies where a role for endocannabinoid activation of PPARs has been implicated after administration of fatty acid amide hydrolase (FAAH) inhibitors [7][8][9][10] or endocannabinoid uptake inhibitors 11,12 to increase local endocannabinoids levels, but where the activating ligand has not been specifically identified.…”

“…The phytocannabinoids 9 -tetrahydrocannabinol (THC), cannabidiol (CBD) and ajulemic acid (a synthetic analogue of a tetrahydrocannabinol metabolite, AJA) can all bind to, increase the transcriptional activity of, and have effects that are inhibited by an antagonist of PPARγ (see Table 2). By contrast, two studies investigating the potential activity of phytocannabinoids at PPARα found that THC does not bind to PPARα, 13 and that AJA does not bind to or activate PPARα.…”