Dopaminergic-GABAergic interplay and alcohol binge drinking

Leggio, GM; Di Marco, R; Gulisano, W; D'Ascenzo, M; Torrisi, SA; Geraci, F; Lavanco, G; Dahl, K; Giurdanella, G; Castorina, A; Aitta-aho, T; Aceto, G; Bucolo, C; Puzzo, D; Grassi, C; Korpi, ER; Drago, F; Salomone, S

Dopaminergic-GABAergic interplay and alcohol binge drinking

Leggio, GM Di Marco, R Gulisano, W D'Ascenzo, M Torrisi, SA Geraci, F Lavanco, G Dahl, K Giurdanella, G Castorina, A

Aitta-aho, T Aceto, G Bucolo, C Puzzo, D Grassi, C Korpi, ER Drago, F Salomone, S

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Publication Type:: Journal Article
Citation:: Pharmacological Research, 2019, 141 pp. 384 - 391
Issue Date:: 2019-03-01

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Field	Value	Language
dc.contributor.author	Leggio, GM	en_US
dc.contributor.author	Di Marco, R	en_US
dc.contributor.author	Gulisano, W	en_US
dc.contributor.author	D'Ascenzo, M	en_US
dc.contributor.author	Torrisi, SA	en_US
dc.contributor.author	Geraci, F	en_US
dc.contributor.author	Lavanco, G	en_US
dc.contributor.author	Dahl, K	en_US
dc.contributor.author	Giurdanella, G	en_US
dc.contributor.author	Castorina, A https://orcid.org/0000-0001-7037-759X	en_US
dc.contributor.author	Aitta-aho, T	en_US
dc.contributor.author	Aceto, G	en_US
dc.contributor.author	Bucolo, C	en_US
dc.contributor.author	Puzzo, D	en_US
dc.contributor.author	Grassi, C	en_US
dc.contributor.author	Korpi, ER	en_US
dc.contributor.author	Drago, F	en_US
dc.contributor.author	Salomone, S	en_US
dc.date.available	2020-05-25T19:07:37Z
dc.date.issued	2019-03-01	en_US
dc.identifier.citation	Pharmacological Research, 2019, 141 pp. 384 - 391	en_US
dc.identifier.issn	1043-6618	en_US
dc.identifier.uri	http://hdl.handle.net/10453/135121
dc.description.abstract	© 2019 Elsevier Ltd The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/− ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R −/− ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R −/− compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R −/− , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.	en_US
dc.relation.ispartof	Pharmacological Research	en_US
dc.relation.isbasedon	10.1016/j.phrs.2019.01.022	en_US
dc.subject.classification	Pharmacology & Pharmacy	en_US
dc.subject.mesh	Nucleus Accumbens	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Receptors, GABA-A	en_US
dc.subject.mesh	Protein Subunits	en_US
dc.subject.mesh	RNA, Messenger	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Receptors, Dopamine D3	en_US
dc.subject.mesh	GABAergic Neurons	en_US
dc.subject.mesh	Binge Drinking	en_US
dc.title	Dopaminergic-GABAergic interplay and alcohol binge drinking	en_US
dc.type	Journal Article
utslib.citation.volume	141	en_US
utslib.for	1115 Pharmacology and Pharmaceutical 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.publication-status	Published	en_US
pubs.volume	141	en_US

Abstract:

© 2019 Elsevier Ltd The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/− ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R −/− ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R −/− compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R −/− , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.

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http://hdl.handle.net/10453/135121