Central amygdala extracellular signal-regulated kinase signaling pathway is critical to incubation of opiate craving.
Central amygdala extracellular signal-regulated kinase signaling pathway is critical to incubation of opiate craving.
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中央杏仁核细胞外信号调节激酶信号通路对于阿片类药物渴望的孵化至关重要
DOI：
10.1523/jneurosci.3027-08.2008
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发表时间：
2008-12-03
期刊：
影响因子：
--
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Li YQ;Li FQ;Wang XY;Wu P;Zhao M;Xu CM;Shaham Y;Lu L
线索诱导的药物寻求在啮齿类动物逐渐增加后退出操作性自我管理的可卡因，海洛因，甲基苯丙胺，酒精，一种现象被称为“孵化的药物渴望。”在这里，我们使用阿片类药物吗啡，并探讨是否孵化的药物渴望也发生在巴甫洛夫条件性位置偏爱（CPP）的程序中，大鼠学习药物的影响与一个独特的环境背景。我们还探讨了杏仁核ERK和CREB在这种孵化中的作用。我们发现，在接受4对低剂量（1或3 mg/kg）但不接受高剂量（10 mg/kg）吗啡的大鼠中，在最后一次药物暴露后的前14天内，吗啡CPP的表达进行性增加。低剂量（3 mg/kg）吗啡CPP的进行性增加与中央杏仁核而非基底外侧杏仁核中ERK磷酸化（ERK活性的测量）和CREB（ERK的下游靶点）磷酸化的增加相关。此外，抑制中央，但不是基底外侧杏仁核ERK和CREB磷酸化的U 0126降低增强（孵育）药物CPP后，14天的吗啡戒断。最后，NMDA刺激中央杏仁核ERK和CREB磷酸化增强了吗啡戒断1天后的药物CPP，U 0126逆转了这种作用。这些发现表明，大鼠对先前与吗啡配对的环境线索的反应在从低剂量而不是高剂量吗啡戒断的前14天内逐渐增加或潜伏。此外，这种“吗啡渴求的潜伏期”是由中央杏仁核ERK通路的急性激活介导的。
Cue-induced drug-seeking in rodents progressively increases after withdrawal from operant self-administration of cocaine, heroin, methamphetamine, and alcohol, a phenomenon termed “incubation of drug craving.” Here, we used the opiate drug morphine and explored whether incubation of drug craving also occurs in a Pavlovian conditioned place preference (CPP) procedure in which rats learn to associate drug effects with a distinct environmental context. We also explored the role of amygdala ERK and CREB in this incubation. We found that the expression of morphine CPP progressively increases over the first 14 days after the last drug exposure in rats receiving 4 pairings of low-dose (1 or 3 mg/kg) but not high-dose (10 mg/kg) morphine with a distinct environment. The progressive increase in low-dose (3 mg/kg) morphine CPP was associated with increased ERK phosphorylation (a measure of ERK activity) and CREB (a downstream target of ERK) phosphorylation in central but not basolateral amygdala. Furthermore, inhibition of central but not basolateral amygdala ERK and CREB phosphorylation by U0126 decreased the enhanced (incubated) drug CPP after 14 days of withdrawal from morphine. Finally, stimulation of central amygdala ERK and CREB phosphorylation by NMDA enhanced drug CPP after 1 day of withdrawal from morphine, an effect reversed by U0126. These findings indicate that the rat’s response to environmental cues previously paired with morphine progressively increases or incubates over the first 14 days of withdrawal from low but not high morphine doses. Additionally, this “incubation of morphine craving” is mediated by acute activation of central amygdala ERK pathway.