Reti Irving M, Crombag Hans S, Takamiya Kogo, Sutton Jeffrey M, Guo Ning, Dinenna Megan L, Huganir Richard L, Holland Peter C, Baraban Jay M
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, USA.
Behav Neurosci. 2008 Aug;122(4):760-8. doi: 10.1037/a0012514.
Although long-lasting effects of drug withdrawal are thought to play a key role in motivating continued drug use, the mechanisms mediating this type of drug-induced plasticity are unclear. Because Narp is an immediate early gene product that is secreted at synaptic sites and binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it has been implicated in mediating enduring forms of synaptic plasticity. In previous studies, the authors found that Narp is selectively induced by morphine withdrawal in the extended amygdala, a group of limbic nuclei that mediate aversive behavioral responses. Accordingly, in this study, the authors evaluate whether long-term aversive effects of morphine withdrawal are altered in Narp knockout (KO) mice. The authors found that acute physical signs of morphine withdrawal are unaffected by Narp deletion. However, Narp KO mice acquire and sustain more aversive responses to the environment conditioned with morphine withdrawal than do wild type (WT) controls. Paradoxically, Narp KO mice undergo accelerated extinction of this heightened aversive response. Taken together, these studies suggest that Narp modulates both acquisition and extinction of aversive responses to morphine withdrawal and, therefore, may regulate plasticity processes underlying drug addiction.
尽管药物戒断的长期影响被认为在促使持续用药方面起着关键作用，但介导这类药物诱导可塑性的机制尚不清楚。由于Narp是一种即刻早期基因产物，在突触部位分泌并与α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体结合，它被认为与介导持久形式的突触可塑性有关。在先前的研究中，作者发现Narp在杏仁核扩展区被吗啡戒断选择性诱导，杏仁核扩展区是一组介导厌恶行为反应的边缘核团。因此，在本研究中，作者评估了吗啡戒断的长期厌恶效应在Narp基因敲除（KO）小鼠中是否发生改变。作者发现，吗啡戒断的急性身体症状不受Narp缺失的影响。然而，与野生型（WT）对照相比，Narp KO小鼠对与吗啡戒断相关的环境产生并维持了更多的厌恶反应。矛盾的是，Narp KO小鼠这种增强的厌恶反应的消退加速。综上所述，这些研究表明，Narp调节对吗啡戒断厌恶反应的获得和消退，因此可能调节药物成瘾背后的可塑性过程。
