Amphetamine regulates ezrin-radixin-moesin proteins signaling in the nucleus accumbens core via glycogen-synthase-kinase 3β

Abstract

Psychomotor stimulants such as cocaine or amphetamine (AMPH) produce the structural changes in the nucleus accumbems by increasing dendritic spine density after developments of behavioral sensitization and self-administration. The ezrin-radixin-moesin (ERM) proteins have been implicated not only in cell-shape determination but also in signaling pathway. However, it has not been determined yet how ERM proteins are regulated by AMPH. Here I show that the phosphorylation levels of ERM proteins are time-dependently decreased in the NAcc core, but not in the shell, by a single injection of AMPH (2 mg/kg, IP). I also found a similar time-dependent effect of AMPH on the phosphorylation levels for Akt and GSK3β in this site. When rats were co-administered with LiCl (100 mg/kg, IP), a GSK3 inhibitor, and either saline or AMPH (2 mg/kg, IP), and the phosphorylation levels for both GSK3β and ERM in the NAcc core were significantly recovered by this treatment. Further, I show that S9 peptide (0.5 or 5.0 g/µl), GSK activator, decreases both pGSK and pERM levels in this site. Further, microinjection into the NAcc core of LY294002 (0.4 or 4.0 g/µl), PI3 kinase inhibitor, decreases, whereas bpV (0.5 or 5.0 g/µl), its activator, increases pERM levels in this site. Together, these results suggest that AMPH reduces pERM levels in the NAcc core via GSK3β. It is well-known that AMPH pre-exposure produces locomotor sensitization when challenged with the same drug after a certain period of withdrawal. Here I show that chronic AMPH-induced behavioral sensitization reduces the basal levels of pERM as well as pAkt and pGSK proteins in the same direction in the NAcc core, suggesting that chronic AMPH may down-regulate pERM levels through PI3 kinase-Akt-GSK signaling pathways in a longer-lasting fashion contributing to produce a more endurable biochemical changes leading to addicted behaviors.