Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-alpha nuclear receptors.
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 alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) 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-alpha agonist WY14643, and these enhancements were blocked by the PPAR-alpha antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-alpha, either directly by administering a PPAR-alpha agonist or indirectly by administering a FAAH inhibitor.
Mazzola
Carmen
C
Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA.
Medalie
Julie
J
Scherma
Maria
M
Panlilio
Leigh V
LV
Solinas
Marcello
M
Tanda
Gianluigi
G
Drago
Filippo
F
Cadet
Jean Lud
JL
Goldberg
Steven R
SR
Yasar
Sevil
S
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007858:Learning / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D047493:PPAR alpha / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C006253:pirinixic acid