GABA受体与药物依赖性的研究进展

药物成瘾是一种全球性的公共卫生问题,其发生机制十分复杂。γ-氨基丁酸(γ-aminobutyric acid,GABA)是中枢神经系统中主要的抑制性神经递质,其通过调节GABA受体(如:GABA_A,GABA_B)的活性参与多种药物成瘾和依赖性的发生与发展过程。吗啡、可卡因、甲基苯丙胺等药物引起的奖赏、戒断和复吸作用与GABA受体的激活或抑制密切相关。本文将对GABA受体在药物依赖中的作用及机制进行综述,从而为治疗药物成瘾提供新的策略。     

甲基苯丙胺成瘾者情绪加工障碍的机制及其临床干预方法的整合研究进展

近年来,在中国以甲基苯丙胺为代表的合成毒品使用人数已经超过海洛因等传统毒品,而且滥用问题日益严重.情绪问题是诱发甲基苯丙胺成瘾者复吸的重要因素.慢性使用甲基苯丙胺导致前额叶-边缘单胺类神经递质系统及相应神经环路结构和功能损害,是成瘾者出现情绪加工障碍的原因.本文从情绪体验、情绪识别与表达和线索诱发的情绪反应性三个方面总结甲基苯丙胺成瘾者情绪加工障碍的表现形式,及相应神经递质系统神经环路基础.指出易激惹和愤怒攻击行为是甲基苯丙胺成瘾过程需要重点关注的情绪问题,并进一步总结了甲基苯丙胺成瘾者情绪障碍的临床治疗和干预的潜在方法,包括药物手段、神经调控技术、认知与行为治疗等,特别是信息科学和脑科学的新技术,如虚拟现实整合多感觉通道的情绪信息,并结合神经调控技术可为甲基苯丙胺成瘾者情绪加工障碍的临床干预提供新的视角.     

精神活性物质对组蛋白乙酰化修饰的影响

当前,精神活性物质的滥用和成瘾呈上升趋势,其既是一个严重的社会问题,又是一个非常重要的医学问题.表观遗传学的研究发现,基因表观事件的发生与精神活性物质的滥用和成瘾有着密切的关系,其中组蛋白乙酰化修饰起了关键作用,基因表观事件的发生与精神活性物质的滥用和成瘾有着密切的关系,其中组蛋白乙酰化起了关键作用.本文着重阐述了可上卡因、苯丙胺、甲基苯丙胺、吗啡和酒精等多种精神活性物质对组蛋白乙酰化的影响.     

阿片成瘾机制研究进展及治疗展望

关于阿片类药物成瘾机制的研究是药物成瘾研究中的一个热点,本文从参与阿片成瘾的神经递质系统及其相互作用、不同阿片受体在成瘾过程中的作用、学习记忆与阿片成瘾的关系、成瘾性药物的细胞内信号转导机制等几个方面介绍了近年来的研究进展,并对阿片类药物成瘾治疗和预防和新方法进行了展望。     

涡虫在研究药物成瘾机制中的应用

药物成瘾危害人类健康并带来经济和社会问题,而滥用药物所造成的身体损害、身体依赖和戒断综合征的治疗等问题的解决仍存在困难.涡虫具有原始的中枢神经系统,其神经递质系统与哺乳类相似,具有易观察可量化的戒断反应,具有易饲养、低成本、无伦理问题等优于哺乳类实验动物的特点,因而迅速成为新的神经药理学在体动物实验模型.本文对涡虫的优点及其在药物成瘾机制等方面的研究进展进行综述,为药物成瘾机制及其治疗的研究提供新的思路.     

多巴胺对吗啡成瘾大鼠海马区痛觉调制的研究进展

当今社会日益增长的吗啡等阿片类药物的非法滥用已经严重威胁到人类的健康。然而,迄今为止尚没有找到能够较为有效的防治阿片成瘾的方法。目前研究已知,阿片成瘾的形成所涉及的脑区及核团包括中脑腹侧被盖区(VTA)、伏隔核(NAc)、海马等,其成瘾涉及的神经递质系统包括多巴胺、5-羟色胺等。本文将就多巴胺及海马在痛觉调制及药物成瘾过程中的作用进行综述,为吗啡的成瘾与戒断的进一研究及治疗提供线索。     

中枢兴奋剂的药理作用及其依赖性特点

中枢兴奋剂的滥用近年来有逐年加剧的趋势,欧、美洲以可卡因、甲基苯丙胺（冰毒）、亚甲二氧甲基苯丙胺（摇头丸）为主;亚洲以“冰毒”为主;独联体多滥用甲基卡西酮。我国５０年代曾有冰毒滥用（当时叫抗疲劳素片,即去氧麻黄素）。９０年代以来,南方一些城市出现了冰...     

miRNAs与药物成瘾

药物成瘾是一种慢性复发性脑病,主要表现为不可控制的对药物持续渴求和戒断后的高复吸。目前观点认为,成瘾是中脑腹侧被盖（ventral tegmental area,VTA）到伏隔核（nucleus accumbens,NAc）脑区多巴胺能奖赏通路中神经可塑性发生改变而导致的一种神经精神疾病。基因表达变化在神经可塑性中发挥着重要作用,但成瘾药物导致相关脑区结构和功能改变的机制还不甚清楚。微小RNAs（microRNAs,miRNAs）是一类非编码RNA,主要通过结合靶基因mRNA 3′非翻译区（3′untranslated region,3′UTR）,在转录后水平阻断其翻译成蛋白质或触发其不稳定而降解。越来越多的研究证实,miRNAs参与调节成瘾相关神经可塑性的变化。本文较系统地阐述miRNAs在药物成瘾中的作用研究进展,将为深入阐明药物成瘾的机制以及药物成瘾临床有效干预和诊治提供新思路。     

甲基苯丙胺的急性和慢性作用机理的研究进展

甲基苯丙胺是一种被广泛使用的神经兴奋剂,它可以使人兴奋,产生欣快感并引起幻觉。这主要是因为脑内的多巴胺和5-羟色胺急剧大量增加所致。长期使用甲基苯丙胺,会对多巴胺和5-羟色胺神经末梢产生持续性的损伤。甲基苯丙胺毒性机理包括兴奋性毒性、线粒体损伤、氧化应激、代谢改变以及炎症反应等,这些均会造成神经末梢损伤。综述了甲基苯丙胺造成神经末梢急性和慢性损伤的机制。     

甲基苯丙胺对中枢神经系统炎症的影响及机制研究进展

甲基苯丙胺(methamphetamine, MA)滥用可严重损害中枢神经系统,但其机制尚未完全阐明,且缺乏有效治疗药物。MA滥用致中枢神经系统受损与小胶质细胞、星形胶质细胞、NF-κB、TNF-α、IL-6和IL-1β及其他一些与中枢神经系统炎症相关因子具有重要联系。现以甲基苯丙胺滥用和关键中枢神经系统炎症反应相关细胞、因子为关注点,重点阐述它们之间的关系,对该领域的研究进展进行综述。     

Epigenetic Alterations in the Brain Associated with HIV-1 Infection and Methamphetamine Dependence

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.     

Epigenetic mechanisms in drug addiction

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.     

Gene expression profiling of the rewarding effect caused by methamphetamine in the mesolimbic dopamine system

Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.     

RNA甲基化修饰调控和规律

表观遗传学修饰包括DNA、RNA和蛋白质的化学修饰,基于非序列改变所致基因表达和功能水平变化。近年来,在DNA和蛋白质修饰基础上,可逆RNA甲基化修饰研究引领了第3次表观遗传学修饰研究的浪潮。RNA存在100余种化学修饰,甲基化是最主要的修饰形式。鉴定RNA甲基化修饰酶及研发其转录组水平高通量检测技术,是揭示RNA化学修饰调控基因表达和功能规律的基础。本文主要总结了近年来本课题组与合作团队及国内外同行在RNA甲基化表观转录组学研究中取得的主要前沿进展,包括发现了RNA去甲基酶、甲基转移酶和结合蛋白,揭示RNA甲基化修饰调控RNA加工代谢,及其调控正常生理和异常病理等重要生命进程。这些系列研究成果证明RNA甲基化修饰类似于DNA甲基化,具有可逆性,拓展了RNA甲基化表观转录组学研究新领域,完善了中心法则表观遗传学规律。     

Retrospective and perspective of plant epigenetics in China

Epigenetics refers to the study of heritable changes in gene function that do not involve changes in the DNA sequence. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors or be part of normal developmental program. In eukaryotes, DNA wraps on a histone octamer (two copies of H2A, H2B, H3 and H4) to form nucleosome, the fundamental unit of chromatin. The structure of chromatin is subjected to a dynamic regulation through multiple epigenetic mechanisms, including DNA methylation, histone posttranslational modifications (PTMs), chromatin remodeling and noncoding RNAs. As conserved regulatory mechanisms in gene expression, epigenetic mechanisms participate in almost all the important biological processes ranging from basal development to environmental response. Importantly, all of the major epigenetic mechanisms in mammalians also occur in plants. Plant studies have provided numerous important contributions to the epigenetic research. For example, gene imprinting, a mechanism of parental allele-specific gene expression, was firstly observed in maize; evidence of paramutation, an epigenetic phenomenon that one allele acts in a single locus to induce a heritable change in the other allele, was firstly reported in maize and tomato. Moreover, some unique epigenetic mechanisms have been evolved in plants. For example, the 24-nt siRNA-involved RNA-directed DNA methylation (RdDM) pathway is plant-specific because of the involvements of two plant-specific DNA-dependent RNA polymerases, Pol IV and Pol V. A thorough study of epigenetic mechanisms is of great significance to improve crop agronomic traits and environmental adaptability. In this review, we make a brief summary of important progress achieved in plant epigenetics field in China over the past several decades and give a brief outlook on future research prospects. We focus our review on DNA methylation and histone PTMs, the two most important aspects of epigenetic mechanisms.