Zhang Lei, Li Juan, Liu Nuyun, Wang Bin, Gu Jingjing, Zhang Min, Zhou Zhitao, Jiang Yong, Zhang Lin, Zhang Lu
Department of Pathophysiology, Southern Medical University, Guangzhou, China.
Neurosignals. 2012;20(1):15-34. doi: 10.1159/000330743. Epub 2011 Nov 9.
Repeated exposure to cocaine can induce persistent alterations in the brain. The structural remodeling of dendrites and dendritic spines is thought to play a critical role in cocaine addiction. We previously demonstrated that signaling via dopamine D1 and D3 receptors have opposite effects on cocaine-induced gene expression. Here, we show that cocaine-induced structural remodeling in the nucleus accumbens (NAc) and caudoputamen (CPu) is mediated by D1 receptors and inhibited by D3 receptors. In addition, chronic exposure to cocaine results in an altered number of asymmetric spine synapses via the actions of both D1 and D3 receptors. The contradictory effects of D1 and D3 receptor signaling on cocaine-induced structural remodeling is associated with NMDA-receptor R1 subunit (NR1) phosphorylation, and is dependent upon the activation of extracellular signal-regulated kinase (ERK). In addition, we found that D1 and D3 receptor signaling has contradictory effects upon the activation of the myocyte enhancer factor 2 (MEF2), which is involved in the dendritic remodeling after cocaine treatment. Together, these data suggest that dopamine D1 and D3 receptors differentially regulate the cocaine-induced structural remodeling of dendrites and spines via mechanisms involving the consecutive actions of NR1 phosphorylation, ERK activation, and MEF2 activity in the NAc and CPu.
反复接触可卡因会导致大脑发生持续性改变。树突和树突棘的结构重塑被认为在可卡因成瘾中起关键作用。我们之前证明，通过多巴胺D1和D3受体的信号传导对可卡因诱导的基因表达有相反的影响。在此，我们表明，可卡因诱导的伏隔核（NAc）和尾壳核（CPu）的结构重塑由D1受体介导，并受D3受体抑制。此外，长期接触可卡因会通过D1和D3受体的作用导致不对称棘突触数量改变。D1和D3受体信号传导对可卡因诱导的结构重塑的矛盾作用与NMDA受体R1亚基（NR1）磷酸化有关，并依赖于细胞外信号调节激酶（ERK）的激活。此外，我们发现D1和D3受体信号传导对肌细胞增强因子2（MEF2）的激活有矛盾作用，MEF2参与可卡因处理后的树突重塑。总之，这些数据表明，多巴胺D1和D3受体通过涉及NAc和CPu中NR1磷酸化、ERK激活和MEF2活性的连续作用机制，对可卡因诱导的树突和棘的结构重塑进行差异调节。
