Pre-synaptic dopamine D3 receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways
Pre-synaptic dopamine D3 receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways
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DOI：
10.1111/j.1471-4159.2011.07618.x
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发表时间：
2012-03-01
影响因子：
4.7
通讯作者：
Missale, Cristina
中科院分区：
文献类型：
--
作者：
Collo, Ginetta;Bono, Federica;Missale, Cristina
暴露于精神兴奋剂导致中脑多巴胺能系统的神经适应性变化，包括多巴胺能神经元的形态学重组。增加树突树枝状和索马面积先前观察到在原代培养的中脑多巴胺能神经元后3天暴露于多巴胺激动剂通过激活D3自身受体（D3 R）。在这项工作中，我们发现，可卡因显着增加树突状分支和索马面积的多巴胺能神经元从E12.5小鼠胚胎通过激活磷酸化的细胞外信号调节激酶（ERK）和胸腺瘤病毒原癌基因（Akt）。这些效应依赖于功能性D3 R表达，因为可卡因在D3 R突变小鼠的原代培养物中或在用D3 R拮抗剂SB-277011-A和S-33084进行药理学阻断后均不产生形态学变化或ERK/Akt磷酸化。通过与磷脂酰肌醇3-激酶抑制剂LY 294002预孵育，抑制了对形态学和ERK/Akt磷酸化的协同效应。这些观察结果证实了在体内的中脑多巴胺能神经元的P1新生儿暴露于可卡因从E12.5到E16.5的形态计量学评估。辅酶A增加野生型小鼠的索马面积，但不增加D3 R突变小鼠的面积，支持原代培养的转化价值。这些研究结果表明，直接参与D3 R和ERK/Akt途径作为可卡因诱导的结构可塑性的关键介质，这表明它们参与精神兴奋剂成瘾。
Exposure to psychostimulants results in neuroadaptive changes of the mesencephalic dopaminergic system including morphological reorganization of dopaminergic neurons. Increased dendrite arborization and soma area were previously observed in primary cultures of mesencephalic dopaminergic neurons after 3-day exposure to dopamine agonists via activation of D3 autoreceptors (D3R). In this work, we showed that cocaine significantly increased dendritic arborization and soma area of dopaminergic neurons from E12.5 mouse embryos by activating phosphorylation of extracellular signal-regulated kinase (ERK) and thymoma viral proto-oncogene (Akt). These effects were dependent on functional D3R expression because cocaine did not produce morphological changes or ERK/Akt phosphorylation neither in primary cultures of D3R mutant mice nor following pharmacologic blockade with D3R antagonists SB-277011-A and S-33084. Cocaine effects on morphology and ERK/Akt phosphorylation were inhibited by pre-incubation with the phosphatidylinositol 3-kinase inhibitor LY294002. These observations were corroborated in vivo by morphometrical assessment of mesencephalic dopaminergic neurons of P1 newborns exposed to cocaine from E12.5 to E16.5. Cocaine increased the soma area of wild-type but not of D3R mutant mice, supporting the translational value of primary culture. These findings indicate a direct involvement of D3R and ERK/Akt pathways as critical mediators of cocaine-induced structural plasticity, suggesting their involvement in psychostimulant addiction.