Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, Valencia 46012, Spain; Department of Neurology, Columbia University Medical Center, New York, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jan 10;96:109753. doi: 10.1016/j.pnpbp.2019.109753. Epub 2019 Aug 22.
Social stress is associated with higher vulnerability to drug use, as it enhances the reinforcing effects of psychostimulants in rodents. Furthermore, continued or severe stress induces a proinflammatory state of microglial activation and augmented cytokine production. The aim of the present work was to evaluate the role of fractalkine [C-X3-C motif ligand 1 (CX3CL1)], an inflammatory chemokine, in the increased conditioned rewarding effects of cocaine in animals exposed to social defeat stress. In addition, we measured the signaling cascade pathway of CX3CL1 in the hippocampus (HPC) (including p-ERK/ERK, p-p38/p38 MAPK, p-p65/p65 NFκB and p-CREB/CREB ratios). The glutamate receptor subunits NR1, NR2B and GluA1 were also assessed. A total of 102 adult male C57BL/6 J wild-type (WT) and Cx3cr1 knockout (KO) mice were divided into different experimental groups according to stress condition (exploration or social defeat). Three weeks after the last social defeat, conditioned place preference (CPP) was induced by a subthreshold dose of cocaine (1 mg/kg). Brain tissue samples were taken 24 h after the CPP procedure to determine the levels of the proteins and transcription factors. Our results showed that, in WT animals, repeated social defeat (RSD) decreased CX3CL1 striatal levels without producing changes in the HPC. In addition, RSD induced an increase in the conditioned rewarding effects of cocaine, regardless of the genotype. After CPP induced by cocaine, defeated Cx3cr1-deficient mice showed a decrease in the p-p65/p65 NFκB and pCREB/CREB ratio in the HPC, and an increase in the hippocampal levels of CX3CL1 and p-p38/p38 MAPK relation. In all defeated mice, there was a decrease in the ionotropic glutamate receptor subunit NR1. In conclusion, these results suggest that the lack of CX3CL1/Cx3cr1 signaling under stress conditions induces changes in protein and transcription factors, indicating that CX3CL1 is needed to shield the response to social defeat.
社会压力与更高的药物使用易感性有关，因为它增强了啮齿动物中精神兴奋剂的强化作用。此外，持续或严重的应激会引起小胶质细胞激活的促炎状态和细胞因子产生的增加。本研究旨在评估趋化因子 fractalkine[C-X3-C 基序配体 1(CX3CL1)]在经历社交挫败应激的动物中可卡因条件性奖赏效应增加中的作用。此外，我们还测量了海马体（HPC）中 CX3CL1 的信号级联途径（包括 p-ERK/ERK、p-p38/p38MAPK、p-p65/p65NFκB 和 p-CREB/CREB 比值）。还评估了谷氨酸受体亚基 NR1、NR2B 和 GluA1。总共 102 只成年雄性 C57BL/6J 野生型（WT）和 Cx3cr1 敲除（KO）小鼠根据应激条件（探索或社交挫败）分为不同的实验组。最后一次社交挫败后 3 周，用亚阈值剂量可卡因（1mg/kg）诱导条件性位置偏好（CPP）。CPP 程序后 24 小时采集脑组织样本，以确定蛋白质和转录因子的水平。我们的结果表明，在 WT 动物中，反复社交挫败（RSD）降低了纹状体中的 CX3CL1 水平，但没有改变 HPC 中的水平。此外，RSD 诱导了可卡因条件性奖赏效应的增加，而与基因型无关。在可卡因诱导 CPP 后，被击败的 Cx3cr1 缺陷小鼠显示 HPC 中 p-p65/p65NFκB 和 pCREB/CREB 比值降低，以及海马体中 CX3CL1 和 p-p38/p38MAPK 关系增加。在所有被击败的小鼠中，离子型谷氨酸受体亚基 NR1 减少。总之，这些结果表明，应激条件下缺乏 CX3CL1/Cx3cr1 信号会导致蛋白质和转录因子发生变化，表明 CX3CL1 对于屏蔽对社交挫败的反应是必要的。
