β-Arrestin-2 inhibits preference for alcohol in mice and suppresses Akt signaling in the dorsal striatum.

In this study, we investigated the role of β-arrestin-2 in alcohol preference using the two-bottle choice and conditioned place preference procedures in wild-type (WT) and β-arrestin-2 knockout (KO) mice. Locomotion and righting reflex tests were performed to test alcohol sensitivity. The possible molecular signals regulated by β-arrestin-2 were analyzed by Western blot. We found that β-arrestin-2 KO mice showed a marked increase in voluntary alcohol consumption without significant differences in preference for saccharin or aversion to quinine. These animals also exhibited higher conditioned place preference scores for alcohol than WT mice. Meanwhile, KO mice showed reduced sensitivity to alcohol and increased blood alcohol clearance. Furthermore, after the free consumption of alcohol, the activities of protein kinase B and glycogen synthase kinase 3β (GSK3β) increased in the dorsal striatum of WT mice, but not in KO mice, which showed high basal activity of Akt in the dorsal striatum. These results suggest that β-arrestin-2 negatively regulates alcohol preference and reward, likely through regulating the activation of signaling pathways including Akt/GSK3β in the dorsal striatum.