Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition.
Persistent reversal of enhanced amphetamine intake by transient CaMKII inhibition.
复制标题
通过瞬态CAMKII抑制作用持续逆转苯丙胺摄入量。
DOI：
10.1523/jneurosci.4386-13.2013
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发表时间：
2013-01-23
期刊：
影响因子：
--
通讯作者：
Vezina P
中科院分区：
文献类型：
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作者：
Loweth JA;Li D;Cortright JJ;Wilke G;Jeyifous O;Neve RL;Bayer KU;Vezina P
苯丙胺暴露会瞬时增加伏隔核(NAcc)壳中CaMKIIα的表达，这会持续增加局部GluA1 S831的磷酸化，并增强对药物的行为反应。在这里，我们评估了使用显性负性CaMKIIα突变体与单纯疱疹病毒载体一起传递到NAcc外壳的瞬时干扰CaMKII信号转导是否可以逆转暴露于苯丙胺后观察到的这些长期的生化和行为影响。正如预期的那样，CaMKIIαK42M在NAcc壳中的瞬时表达导致该位点CaMKIIα的瞬时增加和pCaMKIIα(T286)蛋白水平的降低。值得注意的是，这种对CaMKII活性的短暂抑制导致了NAcc壳中增加的GluA1 S831磷酸化水平的长期逆转，并持久地阻止了通常在先前接触该药物的大鼠中观察到的对苯丙胺增强的运动反应和自我给药。总之，这些结果表明，即使是对CaMKII信号的短暂干扰也可能为药物敏感者带来长期的好处，并表明CaMKII及其下游通路是治疗兴奋剂成瘾的有吸引力的治疗靶点。
Amphetamine exposure transiently increases CaMKIIα expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral (HSV) vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.