Cole R L, Konradi C, Douglass J, Hyman S E
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Charlestown 02129, USA.
Neuron. 1995 Apr;14(4):813-23. doi: 10.1016/0896-6273(95)90225-2.
Induction of prodynorphin gene expression by psychostimulant drugs may represent a compensatory adaptation to excessive dopamine stimulation and may contribute to the aversive aspects of withdrawal. We therefore investigated the molecular mechanisms by which dopamine psychostimulant drugs induce prodynorphin gene expression in vivo and in rat primary striatal cultures. We demonstrate that three recently described cAMP response elements (CREs), rather than a previously reported noncanonical AP-1 site, are critical for dopamine induction of the prodynorphin gene in striatal neurons. CRE-binding protein (CREB) binds to these CREs in striatal cell extracts and is phosphorylated on Ser-133 after dopamine stimulation in a D1 dopamine receptor-dependent manner. Surprisingly, following chronic administration of amphetamine, levels of phosphorylated CREB are increased above basal in rat striatum in vivo, whereas c-fos mRNA is suppressed below basal levels. D1 receptor-mediated CREB phosphorylation appears to mediate adaptations to psychostimulant drugs in the striatum.
精神兴奋药物诱导强啡肽原基因表达可能代表对过量多巴胺刺激的一种代偿性适应，并可能导致戒断反应中的厌恶方面。因此，我们研究了多巴胺精神兴奋药物在体内和大鼠原代纹状体培养物中诱导强啡肽原基因表达的分子机制。我们证明，最近描述的三个环磷酸腺苷反应元件（CREs），而非先前报道的非典型激活蛋白-1（AP-1）位点，对纹状体神经元中多巴胺诱导强啡肽原基因表达至关重要。CRE结合蛋白（CREB）在纹状体细胞提取物中与这些CREs结合，并在多巴胺刺激后以D1多巴胺受体依赖的方式在丝氨酸133位点发生磷酸化。令人惊讶的是，在长期给予苯丙胺后，体内大鼠纹状体中磷酸化CREB的水平高于基础水平，而原癌基因c-fos的信使核糖核酸（mRNA）被抑制到基础水平以下。D1受体介导的CREB磷酸化似乎介导了纹状体对精神兴奋药物的适应性变化。
