Dopaminergic-GABAergic interplay and alcohol binge drinking.

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