Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats
Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats
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DOI：
10.1016/j.drugalcdep.2015.04.012
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发表时间：
2015-07-01
影响因子：
4.2
通讯作者：
Pendyala, Gurudutt
中科院分区：
文献类型：
--
作者：
Charntikov, Sergios;Pittenger, Steven T.;Pendyala, Gurudutt
背景资料：慢性甲基苯丙胺摄入已被证明会诱导神经炎症状态，导致大脑功能的显着变化，包括行为变化。这些变化可以在停止使用药物后持续多年，并可能导致复发的风险。更好地了解与甲基苯丙胺摄入量相关的炎症反应可能有助于设计新的和更有效的治疗strategy.Methods：大鼠进行训练，以自我管理甲基苯丙胺或生理盐水的可变比率3时间表的强化（25天）。这种训练之后是12天的灭绝（即，甲基苯丙胺不可用），在此期间大鼠接受异丁司特（AV 411; 2.5或7.5 mg/kg）或盐水的每日疗程后施用。灭绝后，突触体分离出前额叶皮层（PFC）和突触蛋白的差异模式进行了评估，使用基于质谱的proteomics.Results：异丁司特治疗允许更深的主动杠杆按压灭绝。基于PFC蛋白质组学的定量质谱法确定了一个潜在的命中;突触信号蛋白磷脂酰乙醇胺结合蛋白1（PEBP 1）。虽然甲基苯丙胺摄入与PEBP 1蛋白水平降低相关，但异丁司特治疗逆转了这一效应。此外，PEBP 1表达降低与随后的丝裂原活化蛋白激酶级联（MAPK）的Raf-1、MEK和ERK信号传导组分的活化相关。Raf-1，MEK和ERK的表达水平也衰减异丁司特treatment.Conclusion：PEBP 1，由于其突触定位和其作为一个信号分子的作用，通过ERK/MAPK通路，可能是一个潜在的治疗靶点介导的药物寻求行为与神经炎症。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Background: Chronic methamphetamine intake has been shown to induce a neuroinflammatory state leading to significant changes in brain functioning including behavioral changes. These changes can persist for years after drug use is discontinued and likely contribute to the risk of relapse. A better understanding of inflammation responses associated with methamphetamine intake may help in designing novel and more efficacious treatment strategies.Methods: Rats were trained to self-administer methamphetamine or saline on a variable ratio 3 schedule of reinforcement (25 days). This training was followed by 12 days of extinction (i.e., methamphetamine unavailable) during which rats received daily post-session administration of ibudilast (AV411; 2.5 or 7.5 mg/kg) or saline. Following extinction, synaptosomes were isolated from the prefrontal cortex (PFC) and the differential pattern of synaptic proteins was assessed using mass spectrometry based proteomics.Results: Treatment with ibudilast allowed for deeper extinction of active lever pressing. Quantitative mass spectrometry based proteomics on the PFC identified one potential hit; the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1). While methamphetamine intake was associated with reduced PEBP1 protein levels, treatment with ibudilast reversed this effect. Furthermore, decreased PEBP1 expression was correlated with subsequent activation of Raf-1, MEK, and ERK signaling components of the mitogen-activated protein kinase cascade (MAPK). Raf-1, MEK, and ERK expression levels were also attenuated by ibudilast treatment.Conclusion: PEBP1, given its synaptic localization and its role as a signaling molecule acting via the ERK/MAPK pathway, could be a potential therapeutic target mediating drug-seeking behaviors associated with neuroinflammation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.