Negative relationship between brain alpha(1A)-AR neurotransmission and beta Arr2 levels in anxious adolescent rats subjected to early life stress

Abstract

Early-life stress is correlated with the development of anxiety-related behavior in adolescence, but underlying mechanisms remain poorly known. The alpha(1A)-adrenergic receptor (AR) is linked to mood regulation and its function is assumed to be regulated by beta-arrestins (beta Arrs) via desensitization and downregulation. Here, we investigated correlation between changes in alpha(1A)-AR and beta Arr2 levels in the prefrontal cortex (PFC) and hippocampus of adolescent and adult male rats subjected to maternal separation (MS) and their relationship with anxiety-like behavior in adolescence. MS was performed 3 h per day from postnatal days 2-11 and anxiety-like behavior was evaluated in the elevated plus-maze and open field tests. The protein levels were examined using western blot assay. MS decreased alpha(1A)-AR expression and increased beta Arr2 expression in both brain regions of adolescent rats, while induced reverse changes in adulthood. MS adolescent rats demonstrated higher anxiety-type behavior and lower activity in behavioral tests than controls. Decreased alpha(1A)-AR levels in MS adolescence strongly correlated with reduced time spent in the open field central area, consistent with increased anxiety-like behavior. An anxiety-like phenotype was mimicked by acute and chronic treatment of developing rats with prazosin, an alpha(1A)-AR antagonist, suggesting alpha(1A)-AR downregulation may facilitate anxiety behavior in MS adolescent rats. Together, our results indicate a negative correlation between alpha(1A)-AR neurotransmission and beta Arr2 levels in both adults and anxious-adolescent rats and suggest that increased beta Arr2 levels may contribute to posttranslational regulation of alpha(1A)-AR and modulation of anxiety-like behavior in adolescent rats. This may provide a path to develop more effective anxiolytic treatments.