Amphetamine regulates ezrin-radixin-moesin proteins signaling in the nucleus accumbens core via glycogen-synthase-kinase 3β
중격측좌핵 심부에서 암페타민에 의한 ezrin-radixin-moesin 단백질의 glycogen-synthase-kinase 3β를 통한 신호전달 조절기전에 대한 연구
Dept. of Medical Science/박사
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.