Dopamine-dependent increases in phosphorylation of cAMP response element binding protein (CREB) during precipitated morphine withdrawal in primary cultures of rat striatum
Dopamine-dependent increases in phosphorylation of cAMP response element binding protein (CREB) during precipitated morphine withdrawal in primary cultures of rat striatum
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DOI：
10.1046/j.1471-4159.2003.01992.x
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发表时间：
2003-10-01
影响因子：
4.7
通讯作者：
Carlezon, WA
中科院分区：
文献类型：
--
作者：
Chartoff, EH;Papadopoulou, M;Carlezon, WA
慢性吗啡导致许多脑区cAMP信号通路代偿性上调。cAMP信号上调的一个潜在后果是cAMP反应元件结合蛋白（CREB）磷酸化增加，CREB是一种可能调节与吗啡依赖相关的神经适应性的转录因子。伏隔核（NAc）是纹状体的腹侧部分，接收大量多巴胺能输入，其基因表达的改变可能在阿片类药物戒断的某些动机方面发挥作用。为了确定吗啡戒断是否会导致纹状体组织中CREB磷酸化增加，我们研究了纳洛酮沉淀吗啡戒断对大鼠纹状体神经元原代培养中CREB磷酸化的影响。吗啡沉淀戒断与多巴胺-、SKF 82958 （D-1受体激动剂）-和福斯克林诱导的CREB磷酸化增强有关。在沉淀戒断过程中，D-1受体介导的CREB磷酸化依赖于camp依赖性蛋白激酶（PKA）。沉淀戒断也导致c-fos mRNA对SKF 82958的响应上调。急性或慢性吗啡均未改变CREB蛋白水平。这些结果表明吗啡戒断期间D-1受体介导的信号转导增强。此外，它们与体内证据一致，表明纹状体部分（如NAc） CREB激活的增加与药物戒断相关的烦躁状态有关。
Chronic morphine leads to compensatory up-regulation of cAMP signaling pathways in numerous brain regions. One potential consequence of up-regulated cAMP signaling is increased phosphorylation of cAMP response element binding protein ( CREB), a transcription factor that may regulate neuroadaptations related to morphine dependence. Altered gene expression within the nucleus accumbens (NAc), a ventral component of the striatum that receives substantial dopaminergic input, may play a role in some of the motivational aspects of opiate withdrawal. To determine if morphine withdrawal leads to increased CREB phosphorylation in striatal tissues, we examined the effects of naloxone-precipitated morphine withdrawal on CREB phosphorylation in primary cultures of rat striatal neurons. Precipitated morphine withdrawal was associated with enhanced dopamine-, SKF 82958 ( D-1 receptor agonist)-, and forskolin-induced CREB phosphorylation. During precipitated withdrawal, D-1 receptor-mediated CREB phosphorylation was dependent on cAMP-dependent protein kinase (PKA). Precipitated withdrawal also led to up-regulation of c-fos mRNA in response to SKF 82958. CREB protein levels were not altered by acute or chronic morphine. These results suggest that D-1 receptor-mediated signal transduction is enhanced during morphine withdrawal. Furthermore, they are consistent with in vivo evidence suggesting that increased CREB activation in portions of the striatum (e.g. the NAc) is related to dysphoric states associated with drug withdrawal.