title: Dopamine D3 receptor is necessary for ethanol consumption: an approach with buspirone.
abstract: Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R(-/-)) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R(-/-) and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R(-/-) mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R(-/-); in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Leggio
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camillieri
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Chiara B M
authors.initials: CB
authors.lastname: Platania
authors.affiliation: Department of Bio-Medical Sciences, Catania University, Catania, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Castorina
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Marrazzo
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Sebastiano Alfio
authors.initials: SA
authors.lastname: Torrisi
authors.affiliation: Behavioral Neurobiology Laboratory, Centre for Addiction and Mental Health and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Christina N
authors.initials: CN
authors.lastname: Nona
authors.affiliation: Department of Bio-Medical Sciences, Catania University, Catania, Italy.
authors.forename: Velia
authors.initials: V
authors.lastname: D'Agata
authors.affiliation: Imaging Research Centre and Campbell Family Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Psychology and Pharmacology, University of Toronto, Toronto, Canada.
authors.forename: José
authors.initials: J
authors.lastname: Nobrega
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.affiliation: Translational Addiction Research Laboratory, Centre for Addiction and Mental Health and Departments of Family and Community Medicine, Psychiatry and Pharmacology, University of Toronto, Toronto, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002065:Buspirone / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D050637:Receptors, Dopamine D3; D000431:Ethanol; D002065:Buspirone