Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alcohol Drinking / genetics*
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Amidohydrolases / genetics
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Amidohydrolases / metabolism
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Analgesics / pharmacology
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Animals
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Behavior, Animal / drug effects
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Benzamides / pharmacology
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Benzoxazines
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Brain Chemistry / drug effects
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Brain Chemistry / genetics
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Cannabinoid Receptor Modulators / metabolism*
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Carbamates / pharmacology
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Central Nervous System Depressants / administration & dosage
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Dose-Response Relationship, Drug
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Drug Interactions
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Endocannabinoids*
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Ethanol / administration & dosage
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Gene Expression / drug effects
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Gene Expression / physiology*
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Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
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In Situ Hybridization / methods
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Male
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Morpholines / pharmacology
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Naphthalenes / pharmacology
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Piperidines / pharmacokinetics
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / metabolism*
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Pyrazoles / pharmacokinetics
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RNA, Messenger / metabolism
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Rats
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Receptor, Cannabinoid, CB1 / genetics
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Receptor, Cannabinoid, CB1 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Rimonabant
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Self Administration / methods
Substances
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Analgesics
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Benzamides
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Benzoxazines
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Cannabinoid Receptor Modulators
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Carbamates
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Central Nervous System Depressants
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Endocannabinoids
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Morpholines
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Naphthalenes
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Piperidines
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Pyrazoles
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RNA, Messenger
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Receptor, Cannabinoid, CB1
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cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
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Guanosine 5'-O-(3-Thiotriphosphate)
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Ethanol
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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Amidohydrolases
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fatty-acid amide hydrolase
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Rimonabant