title: Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior.
abstract: The role of the dopamine D1 receptor subtype in alcohol-seeking behaviors was studied in mice genetically deficient in dopamine D1 receptors (D1 -/-). In two-tube free choice limited (1-5 h) and continuous (24 h) access paradigms, mice were exposed to water and increasing concentrations of ethanol (3%, 6% and 12% w/v). Voluntary ethanol consumption and preference over water were markedly reduced in D1 -/- mice as compared to heterozygous (D1 +/-) and wild-type (D1 +/+) controls, whereas overall fluid consumption was comparable. When offered a single drinking tube containing alcohol as their only source of fluid for 24 h, D1 -/- mice continued to drink significantly less alcohol than D1 +/+ and D1 +/- mice. Dopamine D2 receptor blockade with sulpiride caused a small but significant reduction in alcohol intake and preference in D1 +/+ mice and attenuated residual alcohol drinking in D1 -/- mice. Dopamine D1 receptor blockade with SCH-23390 very effectively reduced alcohol intake in D1 +/+ and D1 +/- mice to the level seen in untreated D1 -/- mice. These findings suggest involvement of both dopamine D1 and D2 receptor mechanisms in alcohol-seeking behavior in mice; however, these implicate D1 receptors as having a more important role in the motivation for alcohol consumption.
authors.affiliation: Department of Pharmacology and Medicine, University of Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: El-Ghundi
authors.forename: S R
authors.initials: SR
authors.lastname: George
authors.forename: J
authors.initials: J
authors.lastname: Drago
authors.forename: P J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: T
authors.initials: T
authors.lastname: Fan
authors.forename: T
authors.initials: T
authors.lastname: Nguyen
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: D R
authors.initials: DR
authors.lastname: Sibley
authors.forename: H
authors.initials: H
authors.lastname: Westphal
authors.forename: B F
authors.initials: BF
authors.lastname: O'Dowd
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D000431:Ethanol / Q000097:blood; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009042:Motivation; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000502:physiology*; D012642:Selegiline / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D012642:Selegiline; D000431:Ethanol; D004298:Dopamine