Dopaminergic-GABAergic interplay and alcohol binge drinking. (March 2019)

• Record Type: Journal Article
• Authors: Leggio, Gian Marco; Di Marco, Roberta; Gulisano, Walter; D'Ascenzo, Marcello; Torrisi, Sebastiano Alfio; Geraci, Federica; Lavanco, Gianluca; Dahl, Kristiina; Giurdanella, Giovanni; Castorina, Alessandro; Aitta-aho, Teemu; Aceto, Giuseppe; Bucolo, Claudio; Puzzo, Daniela; Grassi, Claudio; Korpi, Esa R.; Drago, Filippo; Salomone, Salvatore
• Is Part Of: Pharmacological research. Volume 141(2019)
• Page Start: 384
• Page End: 391
• Publication Date: 2019-03
• Subjects: Ro 15-4513 (PubChem CID: 5081) -- SB 277011A (PubChem CID: 75358288) -- Furosemide (PubChem CID: 3440); DID drinking in the dark paradigm -- DR dopamine receptor -- D1-5R dopamine D1-5 receptor -- GABA gamma-aminobutyric acid -- GABAARs GABAA receptors -- ISH in situ hybridization -- mIPSCs miniature inhibitory postsynaptic currents -- MSN medium spiny neuron -- NAc nucleus accumbens -- PFC prefrontal cortex -- VTA ventral tegmental area; Dopamine D3 receptor -- GABAAreceptor -- Alpha6 subunit -- Ethanol -- Nucleus accumbens -- Ro 15-4513; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.01.022
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: The dopamine D3 receptor (D3 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 D3 R increases GABAA α6 subunit in the ventral striatum. Here we tested the hypothesis that D3 R-dependent changes in GABAA 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 D3 R knockout (D3 R −/− ) mice and wild type littermates (D3 R +/+ ). Ro 15-4513, a high affinity α6-GABAA ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D3 R +/+, whereas it was robust in D3 R −/− ; other relevant GABAA 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 D3 R +/+, but increased it in D3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABAA antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D3 R −/− compared to D3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D3 R −/−, but not in D3 R +/+ . We conclude that D3 R-dependent enhanced expression of α6 GABAA subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.