Mervosh Nicholas L, Wilson Rashaun, Rauniyar Navin, Hofford Rebecca S, Kutlu Munir Gunes, Calipari Erin S, Lam TuKiet T, Kiraly Drew D
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Proteomes. 2018 Sep 23;6(4):35. doi: 10.3390/proteomes6040035.
Cocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a soluble cytokine that alters the behavioral response to cocaine and which increases dopamine release from the ventral tegmental area (VTA). Despite these known effects on behavior and neurophysiology, the molecular mechanisms by which G-CSF affects brain function are unclear. In this study mice were treated with repeated injections of G-CSF, cocaine or a combination and changes in protein expression in the VTA were examined using an unbiased proteomics approach. Repeated G-CSF treatment resulted in alterations in multiple signaling pathways related to synaptic plasticity and neuronal morphology. While the treatment groups had marked overlap in their effect, injections of cocaine and the combination of cocaine and G-CSF lead to distinct patterns of significantly regulated proteins. These experiments provide valuable information as to the molecular pathways that G-CSF activates in an important limbic brain region and will help to guide further characterization of G-CSF function and evaluation as a possible translational target.
可卡因成瘾的特征是中脑边缘多巴胺回路的异常可塑性，导致寻求和使用毒品的动机失调。尽管可卡因使用障碍给社会造成了巨大损失，但目前尚无可用的药物治疗方法。我们最近发现粒细胞集落刺激因子（G-CSF）是一种可溶性细胞因子，它能改变对可卡因的行为反应，并增加腹侧被盖区（VTA）的多巴胺释放。尽管已知其对行为和神经生理学有这些影响，但G-CSF影响脑功能的分子机制尚不清楚。在本研究中，对小鼠反复注射G-CSF、可卡因或两者的组合，并用无偏差蛋白质组学方法检测VTA中的蛋白质表达变化。反复给予G-CSF治疗导致与突触可塑性和神经元形态相关的多个信号通路发生改变。虽然各治疗组的作用有明显重叠，但注射可卡因以及可卡因与G-CSF的组合导致了显著调节蛋白的不同模式。这些实验为G-CSF在重要边缘脑区激活的分子途径提供了有价值的信息，并将有助于指导对G-CSF功能的进一步表征以及作为可能的转化靶点的评估。
