Reti Irving M, Baraban Jay M
Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neuropsychopharmacology. 2003 Sep;28(9):1606-13. doi: 10.1038/sj.npp.1300205. Epub 2003 May 14.
The negative affective states associated with drug withdrawal produce long-lasting behavioral effects thought to play a central role in the development and maintenance of dependence. However, little is known about the molecular mechanisms mediating the long-term effects of drug withdrawal. Neuronal activity-regulated pentraxin (Narp) is a secreted neuronal immediate early gene (IEG) product that regulates AMPA receptor clustering at synapses. As both IEGs and changes in AMPA receptor trafficking mediate enduring forms of neuronal plasticity, we have assessed whether Narp could be involved in the molecular adaptations accompanying drug withdrawal. To this end, we checked the effect of opiate withdrawal on Narp expression in the extended amygdala, a brain region closely linked to the aversive effects of drug withdrawal. We found a marked increase in the number of Narp-positive cells in this region following opiate withdrawal triggered by either low doses of opiate antagonists or by 'natural withdrawal', removal of the morphine pellets used to induce dependence. In contrast, Arc, another 'effector' IEG, was not induced by opiate withdrawal. As expected, pretreatment of animals with clonidine, which blocks opiate withdrawal, suppresses Narp induction in this paradigm. These results implicate Narp in mediating the long-term, aversive behavioral effects induced by opiate withdrawal.
与药物戒断相关的负面情绪状态会产生持久的行为影响，被认为在成瘾的形成和维持中起核心作用。然而，对于介导药物戒断长期影响的分子机制却知之甚少。神经元活性调节五聚体蛋白（Narp）是一种分泌型神经元即早基因（IEG）产物，可调节突触处AMPA受体的聚集。由于即早基因和AMPA受体转运的变化都介导神经元可塑性的持久形式，我们评估了Narp是否参与药物戒断伴随的分子适应性变化。为此，我们检测了阿片类药物戒断对终纹床核扩展部Narp表达的影响，终纹床核扩展部是一个与药物戒断厌恶效应密切相关的脑区。我们发现，低剂量阿片类拮抗剂引发的阿片类药物戒断或“自然戒断”（去除用于诱导成瘾的吗啡丸）后，该区域Narp阳性细胞数量显著增加。相反，另一种“效应器”即早基因Arc并未被阿片类药物戒断所诱导。正如预期的那样，用可乐定预处理动物（可乐定可阻断阿片类药物戒断）可抑制该模型中Narp的诱导。这些结果表明Narp参与介导阿片类药物戒断诱导的长期厌恶行为效应。
