title: Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol.
abstract: The aim of this study was to examine the role of fatty acid amide hydrolase (FAAH) on ethanol sensitivity, preference, and dependence. The deletion of FAAH gene or the inhibition of FAAH by carbamoyl-biphenyl-3-yl-cyclohexylcarbamate (URB597) (0.1 mg/kg) markedly increased the preference for ethanol. The study further reveals that URB597 specifically acts through FAAH and that cannabinoid-1 (CB(1)) receptor is critical for N-arachidonoyl ethanolamide (AEA) mediated ethanol-reinforced behavior as revealed by lack of URB597 effect in both FAAH and CB(1)-/- mice compared with vehicle-treated -/- mice. The FAAH -/- mice displayed a lower sensitivity to hypothermic and sedative effects to acute ethanol challenge. The FAAH -/- mice also exhibited a reduction in the severity of handling-induced convulsions following withdrawal from chronic ethanol exposure. The CB(1) receptor and proenkephalin gene expressions, and CB(1) receptor and mu-opioid (MO) receptor-mediated G-protein activation were found to be significantly lower in the caudate-putamen, nucleus accumbens core and shell of FAAH -/- than +/+ mice. Interestingly, the MO receptor-stimulated G-protein signaling was greater in the striatum of FAAH -/- than +/+ mice following voluntary ethanol consumption. These findings suggest that an elevation in the AEA content and its action on the limbic CB(1) receptor and MO receptor might contribute to ethanol-reinforced behavior. Treatment with drugs that decrease AEA tone might prove useful in reducing excessive ethanol consumption.
authors.affiliation: Division of Analytical Psychopharmacology, New York State Psychiatric Institute, New York, USA.
authors.forename: K Yaragudri
authors.initials: KY
authors.lastname: Vinod
authors.forename: Elena
authors.initials: E
authors.lastname: Sanguino
authors.forename: Ratnakumar
authors.initials: R
authors.lastname: Yalamanchili
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: Basalingappa L
authors.initials: BL
authors.lastname: Hungund
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism*; D000581:Amidohydrolases / Q000172:deficiency / Q000502:physiology*; D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D002755:Choice Behavior / Q000187:drug effects*; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D000701:Analgesics, Opioid; D001549:Benzamides; D048588:Benzoxazines; D002219:Carbamates; D002492:Central Nervous System Depressants; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins; D000431:Ethanol; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009025:Morpholines; D009281:Naphthalenes; D011498:Protein Precursors; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C029992:proenkephalin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone