Wolf Daniel H, Nestler Eric J, Russell David S
Interdepartmental Neuroscience Program, Yale University School of Medicine, and Connecticut Mental Health Center, New Haven, CT 06508, USA.
Brain Res. 2007 Jul 2;1156:9-20. doi: 10.1016/j.brainres.2007.04.059. Epub 2007 May 4.
Alterations in neurotrophic signaling pathways may contribute to the changes in the mesolimbic dopamine system induced by chronic morphine exposure. In a rat model of morphine dependence, we previously identified increased levels of phospholipase C gamma-1 (PLCgamma1) immunoreactivity specifically within the ventral tegmental area (VTA) following chronic morphine treatment. Using an antibody specific for the tyrosine-phosphorylated, activated form of PLCgamma1, we now show that chronic morphine also significantly upregulates PLCgamma1 activity in the VTA, as well as in the nucleus accumbens and hippocampus, regions which are also implicated in the reinforcing properties of morphine. In contrast, no increase in PLCgamma1 activity was found in the substantia nigra or dorsal striatum. HSV-mediated overexpression of PLCgamma1 in PC12 cells induced ERK activation via a mechanism dependent, in part, on both MAP-ERK kinase (MEK) and protein kinase C. PLCgamma1 overexpression in the VTA similarly induced ERK activation in the VTA in vivo. As chronic morphine treatment has been shown to increase ERK activity within the VTA, the current results suggest that increased PLCgamma1 activity may be an upstream mediator of this effect.
神经营养信号通路的改变可能导致慢性吗啡暴露引起的中脑边缘多巴胺系统变化。在吗啡依赖的大鼠模型中，我们之前发现，慢性吗啡治疗后，腹侧被盖区（VTA）内磷脂酶Cγ-1（PLCγ1）免疫反应性水平升高。现在，我们使用一种针对酪氨酸磷酸化、活化形式的PLCγ1的特异性抗体，发现慢性吗啡还显著上调了VTA以及伏隔核和海马体中PLCγ1的活性，这些区域也与吗啡的强化特性有关。相比之下，在黑质或背侧纹状体中未发现PLCγ1活性增加。单纯疱疹病毒（HSV）介导的PLCγ1在PC12细胞中的过表达通过一种部分依赖于丝裂原活化蛋白激酶激酶（MEK）和蛋白激酶C的机制诱导细胞外信号调节激酶（ERK）激活。VTA中PLCγ1的过表达在体内同样诱导VTA中ERK激活。由于慢性吗啡治疗已被证明会增加VTA内的ERK活性，目前的结果表明，增加的PLCγ1活性可能是这种效应的上游介质。
