Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase.
Endocannabinoid signaling plays the important role in regulation of ethanol intake. Fatty acid amide hydrolase (FAAH) is a key membrane protein for metabolism of endocannabinoids, including anandamide, and blockade of FAAH increases the level of anandamide in the brain. To determine if FAAH regulates ethanol consumption, we studied mutant mice with deletion of the FAAH gene. Null mutant mice showed higher preference for alcohol and voluntarily consumed more alcohol than wild-type littermates. There was no significant difference in consumption of sweet or bitter solutions. To determine the specificity of FAAH for ethanol intake, we studied additional ethanol-related behaviors. There were no differences between null mutant and wild-type mice in severity of ethanol-induced acute withdrawal, conditioned taste aversion to alcohol, conditioned place preference, or sensitivity to hypnotic effect of ethanol. However, null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol. All three behavioral phenotypes (increased preference for ethanol, decreased sensitivity to ethanol-induced sedation, and faster recovery from ethanol-induced motor incoordination) seen in mutant mice were reproduced in wild-type mice by injection of a specific inhibitor of FAAH activity--URB597. These data suggest that increased endocannabinoid signaling increased ethanol consumption owing to decreased acute ethanol intoxication.
Blednov
Yuri A
YA
Department of Neurobiology, Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712-0159, USA. yablednov@mail.utexas.edu
Cravatt
Benjamin F
BF
Boehm
Stephen L
SL
Walker
Danielle
D
Harris
R Adron
RA
D020268:Alcohol-Induced Disorders, Nervous System / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009069:Movement Disorders / Q000201:enzymology / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012727:Sex Characteristics; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D000431:Ethanol; D005227:Fatty Acids; D000099252:Fatty Acid Amide Hydrolases