NEURONAL ADAPTATION TO AMPHETAMINE AND DOPAMINE - MOLECULAR MECHANISMS OF PRODYNORPHIN GENE-REGULATION IN RAT STRIATUM
NEURONAL ADAPTATION TO AMPHETAMINE AND DOPAMINE - MOLECULAR MECHANISMS OF PRODYNORPHIN GENE-REGULATION IN RAT STRIATUM
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DOI：
10.1016/0896-6273(95)90225-2
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发表时间：
1995-04-01
期刊：
影响因子：
16.2
通讯作者：
HYMAN, SE
中科院分区：
文献类型：
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作者：
COLE, RL;KONRADI, C;HYMAN, SE
精神兴奋药物诱导前啡基因表达可能是对过度多巴胺刺激的代偿性适应，并可能导致戒断的厌恶方面。因此，我们研究了多巴胺精神兴奋剂药物在体内和大鼠初级纹状体培养中诱导前啡肽基因表达的分子机制。我们证明了三个最近描述的cAMP反应元件（CREs），而不是先前报道的非规范AP-1位点，是纹状体神经元中多巴胺诱导前啡肽基因的关键。CREB结合蛋白（CREB）在纹状体细胞提取物中与这些CREB结合，并在多巴胺刺激后以D1多巴胺受体依赖的方式在Ser-133上磷酸化。令人惊讶的是，长期服用安非他明后，体内大鼠纹状体中磷酸化CREB的水平高于基础水平，而c-fos mRNA被抑制在基础水平以下。D1受体介导的CREB磷酸化似乎介导纹状体对精神兴奋剂药物的适应。
Induction of prodynorphin gene expression by psychostimulant drugs may re present 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, revels 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.