Dopaminergic-GABAergic interplay and alcohol binge drinking
Pharmacological Research. 2019-03-01; 141: 384-391
DOI: 10.1016/j.phrs.2019.01.022
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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 D3R-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 D3R
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.