Dopaminergic-GABAergic interplay and alcohol binge drinking

The dopamine D-3 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 GABA(A) alpha 6 subunit in the ventral striatum. Here we tested the hypothesis that D3R-dependent changes in GABA(A) alpha 6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D3R knockout (D3R-/-) mice and wild type littermates (D3R+/+). Ro 15-4513, a high affinity alpha 6-GABA(A) ligand was used to study alpha 6 activity. At baseline, NAc alpha 6 expression was negligible in D3R+/+, whereas it was robust in D3R-/-; other relevant GABA(A) subunits were not changed. In situ hybridization and qPCR confirmed alpha 6 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 alpha 6-GABA(A) 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 alpha 6 GABA(A) subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.