TY - JOUR
T1 - Dopaminergic-GABAergic interplay and alcohol binge drinking.
AU - Leggio, Gian Marco
AU - Di Marco, Roberta
AU - Gulisano, Walter
AU - D'Ascenzo, Marcello
AU - Torrisi, Sebastiano Alfio
AU - Geraci, Federica
AU - Lavanco, Gianluca
AU - Dahl, Kristiina
AU - Giurdanella, Giovanni
AU - Castorina, Alessandro
AU - Aitta-Aho, Teemu
AU - Aceto, Giuseppe
AU - Bucolo, Claudio
AU - Puzzo, Daniela
AU - Grassi, Claudio
AU - Korpi, Esa R.
AU - Drago, Filippo
AU - Drago, Fabrizio
AU - Salomone, Salvatore
PY - 2019
Y1 - 2019
N2 - The dopamine D3 receptor (D3R), 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 D3R increases GABAA α6 subunit in the ventral striatum. Here we tested the hypothesis that D3Rdependent 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 knockout (D3R -/-) mice and wild type littermates (D3R +/+). Ro 15-4513, a high affinity α6-GABAA ligand was used to study α6
activity. At baseline, NAc α6 expression was negligible in D3R+/+, whereas it was robust in D3R−/−; 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 D3R+/+, but increased it in D3R−/−; 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 D3R-/- compared to D3R+/+; Ro 15-4513 reduced the peak amplitude in the NAc of D3R-/-, but not in D3R+/+. We conclude that D3R-dependent enhanced expression of α6 GABAA subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.
AB - The dopamine D3 receptor (D3R), 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 D3R increases GABAA α6 subunit in the ventral striatum. Here we tested the hypothesis that D3Rdependent 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 knockout (D3R -/-) mice and wild type littermates (D3R +/+). Ro 15-4513, a high affinity α6-GABAA ligand was used to study α6
activity. At baseline, NAc α6 expression was negligible in D3R+/+, whereas it was robust in D3R−/−; 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 D3R+/+, but increased it in D3R−/−; 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 D3R-/- compared to D3R+/+; Ro 15-4513 reduced the peak amplitude in the NAc of D3R-/-, but not in D3R+/+. We conclude that D3R-dependent enhanced expression of α6 GABAA subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.
KW - Alpha6 subunit
KW - Dopamine D3 receptor
KW - Dopaminergic-GABAergic
KW - Ethanol
KW - GABA(A)receptor
KW - Nucleus accumbens
KW - Alpha6 subunit
KW - Dopamine D3 receptor
KW - Dopaminergic-GABAergic
KW - Ethanol
KW - GABA(A)receptor
KW - Nucleus accumbens
UR - http://hdl.handle.net/10807/129049
U2 - 10.1016/j.phrs.2019.01.022
DO - 10.1016/j.phrs.2019.01.022
M3 - Article
SN - 1096-1186
SP - 384
EP - 391
JO - Pharmacological Research
JF - Pharmacological Research
ER -