title: Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice.
abstract: Cannabinoids and ethanol can activate the same reward pathways, which could suggest endocannabinoid involvement in the rewarding effects of ethanol. The high ethanol preference of young (6-10 weeks) C57BL6J mice is reduced by the cannabinoid receptor 1 (CB1) antagonist SR141716A to levels observed in their CB1 knockout littermates or in old (26-48 weeks) wild-type mice, in both of which ethanol preference is unaffected by SR141716A. Similarly, SR141716A inhibits food intake in food-restricted young, but not old, wild-type mice. There are no age-dependent differences in the tissue levels of the endocannabinoids anandamide and 2-arachidonoylglycerol or the density of CB1 in the hypothalamus, limbic forebrain, amygdala, and cerebellum. CB1-stimulated guanosine 5'-[gamma-thio]triphosphate (GTP[gammaS]) binding is selectively reduced in the limbic forebrain of old compared with young wild-type mice. There is no age-dependent difference in G(i) or G(o) subunit protein expression in the limbic forebrain, and the selective reduction in GTP[gammaS] labeling in tissue from old mice is maintained in a receptorG protein reconstitution assay by using functional bovine brain G protein. These findings suggest that endocannabinoids acting at CB1 contribute to ethanol preference, and decreased coupling of CB1 to G proteins in the limbic forebrain by mechanisms other than altered receptor or G protein levels may be involved in the age-dependent decline in the appetite for both ethanol and food.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000375:Aging; D000428:Alcohol Drinking; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D063388:Endocannabinoids; D000431:Ethanol / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005247:Feeding Behavior; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D037342:Pertussis Toxin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000494:pharmacology; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000431:Ethanol; D013759:Dronabinol; D037342:Pertussis Toxin; C062018:HU 211; D000077285:Rimonabant