Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois 60637, USA.
J Neurosci. 2013 Jan 23;33(4):1411-6. doi: 10.1523/JNEUROSCI.4386-13.2013.
Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) α 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 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.
安非他命暴露会短暂地增加伏隔核壳（NAcc）中的 Ca(2+)/钙调蛋白依赖性蛋白激酶 II（CaMKII）α 的表达，这种表达会持续增加局部 GluA1 S831 磷酸化，并增强对药物的行为反应。在这里，我们评估了使用单纯疱疹病毒载体递送至 NAcc 壳的显性负性 CaMKIIα 突变体短暂干扰 CaMKII 信号是否可以逆转安非他命暴露后观察到的这些持久的生化和行为效应。正如预期的那样，CaMKIIα K42M 在 NAcc 壳中的瞬时表达会导致该部位的 CaMKIIα 和 pCaMKIIα（T286）蛋白水平相应的短暂增加。值得注意的是，这种 CaMKII 活性的短暂抑制会持久地逆转 NAcc 壳中 GluA1 S831 磷酸化水平的增加，并持续阻止以前暴露于药物的大鼠对安非他命的增强的运动反应和自我给药。总之，这些结果表明，即使是短暂干扰 CaMKII 信号也可能为药物敏感个体带来持久的益处，并表明 CaMKII 及其下游途径是治疗兴奋剂成瘾的有吸引力的治疗靶点。
