Dopamine D3 receptor is necessary for ethanol consumption: An approach with buspirone

Leggio, GM; Camillieri, G; Platania, CBM; Castorina, A; Marrazzo, G; Torrisi, SA; Nona, CN; D'Agata, V; Nobrega, J; Stark, H; Bucolo, C; Le Foll, B; Drago, F; Salomone, S

Dopamine D3 receptor is necessary for ethanol consumption: An approach with buspirone

Leggio, GM Camillieri, G Platania, CBM Castorina, A

Marrazzo, G Torrisi, SA Nona, CN D'Agata, V Nobrega, J Stark, H Bucolo, C Le Foll, B Drago, F Salomone, S

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Publication Type:: Journal Article
Citation:: Neuropsychopharmacology, 2014, 39 (8), pp. 2017 - 2028
Issue Date:: 2014-01-01

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Field	Value	Language
dc.contributor.author	Leggio, GM	en_US
dc.contributor.author	Camillieri, G	en_US
dc.contributor.author	Platania, CBM	en_US
dc.contributor.author	Castorina, A https://orcid.org/0000-0001-7037-759X	en_US
dc.contributor.author	Marrazzo, G	en_US
dc.contributor.author	Torrisi, SA	en_US
dc.contributor.author	Nona, CN	en_US
dc.contributor.author	D'Agata, V	en_US
dc.contributor.author	Nobrega, J	en_US
dc.contributor.author	Stark, H	en_US
dc.contributor.author	Bucolo, C	en_US
dc.contributor.author	Le Foll, B	en_US
dc.contributor.author	Drago, F	en_US
dc.contributor.author	Salomone, S	en_US
dc.date.available	2014-02-24	en_US
dc.date.issued	2014-01-01	en_US
dc.identifier.citation	Neuropsychopharmacology, 2014, 39 (8), pp. 2017 - 2028	en_US
dc.identifier.issn	0893-133X	en_US
dc.identifier.uri	http://hdl.handle.net/10453/118718
dc.description.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 (D 3R-/-) 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 D 3R-/- mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D 3R-/-; 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. © 2014 American College of Neuropsychopharmacology. All rights reserved.	en_US
dc.relation.ispartof	Neuropsychopharmacology	en_US
dc.relation.isbasedon	10.1038/npp.2014.51	en_US
dc.subject.classification	Psychiatry	en_US
dc.subject.mesh	Corpus Striatum	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Ethanol	en_US
dc.subject.mesh	Buspirone	en_US
dc.subject.mesh	Brain-Derived Neurotrophic Factor	en_US
dc.subject.mesh	Neuropeptides	en_US
dc.subject.mesh	Alcohol Drinking	en_US
dc.subject.mesh	Choice Behavior	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Receptors, Dopamine D3	en_US
dc.subject.mesh	Drug-Seeking Behavior	en_US
dc.subject.mesh	Receptors for Activated C Kinase	en_US
dc.title	Dopamine D3 receptor is necessary for ethanol consumption: An approach with buspirone	en_US
dc.type	Journal Article
utslib.citation.volume	8	en_US
utslib.citation.volume	39	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	170101 Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)	en_US
utslib.for	11 Medical and Health Sciences	en_US
utslib.for	17 Psychology and Cognitive Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	8	en_US
pubs.publication-status	Published	en_US
pubs.volume	39	en_US

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 (D 3R-/-) 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 D 3R-/- mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D 3R-/-; 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. © 2014 American College of Neuropsychopharmacology. All rights reserved.

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http://hdl.handle.net/10453/118718