Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference.
Endocannabinoid signaling has recently been implicated in ethanol-seeking behavior. We analyzed the expression of endocannabinoid-related genes in key brain regions of reward and dependence, and compared them between the alcohol-preferring AA (Alko Alcohol) and nonpreferring ANA (Alko Non-Alcohol) rat lines. A decreased expression of fatty acid amidohydrolase (FAAH), the main endocannabinoid-degrading enzyme, was found in prefrontal cortex (PFC) of AA rats, and was accompanied by decreased enzyme activity in this region. Binding of the endocannabinoid-cannabinoid 1 (CB1) receptor ligand (3)[H]SR141716A, and [35S]GTPgammaS incorporation stimulated by the CB1 agonist WIN 55,212-2 were downregulated in the same area. Together, this suggests an overactive endocannabinoid transmission in the PFC of AA animals, and a compensatory downregulation of CB1 signaling. The functional role of impaired FAAH function for alcohol self-administration was validated in two independent ways. The CB1 antagonist SR141716A potently and dose-dependently suppressed self-administration in AA rats when given systemically, or locally into the PFC, but not in the striatum. Conversely, intra-PFC injections of the competitive FAAH inhibitor URB597 increased ethanol self-administration in nonselected Wistar rats. These results show for the first time that impaired FAAH function may confer a phenotype of high voluntary alcohol intake, and point to a FAAH both as a potential susceptibility factor and a therapeutic target.
Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD 20892-1108, USA.
Anita C
AC
Hansson
Francisco J
FJ
Bermúdez-Silva
Hanna
H
Malinen
Petri
P
Hyytiä
Irene
I
Sanchez-Vera
Roberto
R
Rimondini
Fernando
F
Rodriguez de Fonseca
George
G
Kunos
Wolfgang H
WH
Sommer
Markus
M
Heilig
D000428:Alcohol Drinking / Q000235:genetics*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D063388:Endocannabinoids; D000431:Ethanol / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000493:pharmacokinetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000077285:Rimonabant; D012646:Self Administration / Q000379:methods; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D001549:Benzamides; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D002492:Central Nervous System Depressants; D063388:Endocannabinoids; D000431:Ethanol; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone