Abstract：
Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry-based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus (LH) and the striatum (ST). We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the LH by adeno-associated virus (AAV) delivery of an shRNA to Arylsulfatase B (N-acetylgalactosamine-4-sulfatase, ARSB) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated vs. saline-treated mice, including MYPR, KCC2A, SYN2, TENR, CALX, ANXA7, HDGF, NCAN, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy.
摘要：
物质使用障碍是一个主要问题，很少有治疗选择。硫酸乙酰肝素（HS）和硫酸软骨素（CS）与多种生长因子及其受体相互作用，对细胞信号传导具有深远的影响。因此，靶向这些动态相互作用可能代表一种潜在的新型治疗方式.在本研究中,我们进行了基于质谱的糖组学和蛋白质组学分析，以了解可卡因和甲基苯丙胺（METH）对HS的影响，CS,以及与药物成瘾密切相关的两个大脑区域的蛋白质组：下丘脑外侧（LH）和纹状体（ST）。我们观察到可卡因和METH显着改变了HS和CS的丰度以及硫酸盐的含量和组成。特别是,重复METH或可卡因治疗可减少CS4-O-硫酸化，并增加CS6-O-硫酸化。由于C4S和C6S运动对轴突生长的影响不同，再生和可塑性，这些变化可能有助于这些脑区的药物诱导的神经可塑性。值得注意的是,我们观察到通过腺相关病毒（AAV）将shRNA递送至芳基硫酸酯酶B（N-乙酰半乳糖胺-4-硫酸酯酶，ARSB）在可卡因戒断过程中，在新颖性诱导的条件性位置偏爱测试中，改善了焦虑并防止了对可卡因的偏爱表达。最后,蛋白质组学分析显示，在甲基和可卡因治疗的患者中存在许多异常蛋白盐水处理的小鼠，包括MYPR,KCC2A,SYN2,TENR,CALX,ANXA7,HDGF,NCAN,和CSPG5，以及顶部扰动途径之间的氧化磷酸化。一起来看,这些数据支持HS的作用，CS,以及兴奋剂滥用中的相关蛋白，并表明HSPGs的操纵可以代表一种新的治疗策略。
