PMID- 24584330 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20211021 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 39 IP - 8 DP - 2014 Jul TI - Dopamine D3 receptor is necessary for ethanol consumption: an approach with buspirone. PG - 2017-28 LID - 10.1038/npp.2014.51 [doi] AB - 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. FAU - Leggio, Gian Marco AU - Leggio GM AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Camillieri, Giovanni AU - Camillieri G AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Platania, Chiara B M AU - Platania CB AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Castorina, Alessandro AU - Castorina A AD - Department of Bio-Medical Sciences, Catania University, Catania, Italy. FAU - Marrazzo, Giuseppina AU - Marrazzo G AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Torrisi, Sebastiano Alfio AU - Torrisi SA AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Nona, Christina N AU - Nona CN AD - Behavioral Neurobiology Laboratory, Centre for Addiction and Mental Health and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. FAU - D'Agata, Velia AU - D'Agata V AD - Department of Bio-Medical Sciences, Catania University, Catania, Italy. FAU - Nobrega, Jose AU - Nobrega J AD - 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. FAU - Stark, Holger AU - Stark H AD - Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. FAU - Bucolo, Claudio AU - Bucolo C AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Le Foll, Bernard AU - Le Foll B AD - 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. FAU - Drago, Filippo AU - Drago F AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. FAU - Salomone, Salvatore AU - Salomone S AD - Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy. LA - eng GR - 1R21DA033515-01/DA/NIDA NIH HHS/United States GR - Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140303 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuropeptides) RN - 0 (RACK1 protein, mouse) RN - 0 (Receptors for Activated C Kinase) RN - 0 (Receptors, Dopamine D3) RN - 3K9958V90M (Ethanol) RN - TK65WKS8HL (Buspirone) SB - IM MH - Alcohol Drinking/*metabolism MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Buspirone/pharmacology MH - Choice Behavior/drug effects MH - Corpus Striatum/metabolism MH - Drug-Seeking Behavior/drug effects/*physiology MH - Ethanol/*administration & dosage MH - Male MH - Mice MH - Mice, Knockout MH - Neuropeptides/metabolism MH - Receptors for Activated C Kinase MH - Receptors, Dopamine D3/antagonists & inhibitors/*genetics PMC - PMC4059912 EDAT- 2014/03/04 06:00 MHDA- 2015/02/13 06:00 PMCR- 2014/07/01 CRDT- 2014/03/04 06:00 PHST- 2013/09/26 00:00 [received] PHST- 2014/02/12 00:00 [revised] PHST- 2014/02/24 00:00 [accepted] PHST- 2014/03/04 06:00 [entrez] PHST- 2014/03/04 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] PHST- 2014/07/01 00:00 [pmc-release] AID - npp201451 [pii] AID - 10.1038/npp.2014.51 [doi] PST - ppublish SO - Neuropsychopharmacology. 2014 Jul;39(8):2017-28. doi: 10.1038/npp.2014.51. Epub 2014 Mar 3.