药物依赖过程中多巴胺受体的作用及其研究进展

<正> 大多数的成瘾药物与脑内多巴胺系统的活动性改变密切相关,而且中脑边缘多巴胺系统(meolimbicdopamine system,MLDS)是公认的与成瘾有关的最重要的脑区。在急性给药情况下,成瘾药物一般都能     

阿片类物质依赖与相关神经递质

近年来,外源性阿片类物质(如吗啡、海洛因)滥用已成为日益严重的社会问题.它不仅严重摧残滥用者本人的身心健康,同时也给家庭、社会带来灾难性后果.     

NMDA型谷氨酸受体NR3亚基与药物依赖相关研究进展

<正>NMDA受体是一类门控离子通道型谷氨酸受体,参与调节中枢神经系统的多种重要功能:如神经元生长发育、神经可塑性及学习记忆等。NMDA受体是异多聚体,由核心亚基NR1结合强化亚基NR2及(或)调节亚基NR3组成。NR1亚基形成离子通道。NR2亚基在配体识别、调控及与其他蛋白相互作用等方面发挥重要作用。和NR1和NR2亚基相比,NR3亚基最晚发现;NR3亚基可形成NR1/NR3     

中枢5-HT受体和药物依赖

<正>药物成瘾是一种复杂的神经适应性疾病,滥用药物慢性处理一方面改变机体神经系统的结构和功能,另一方面机体在药物作用下与用药有关的环境线索产生特异性联系,当再次暴露到用药环境时产生强烈的心理渴求和用药行为。滥用药物奖赏主要     

吗啡依赖与阿片受体和去甲肾上腺素能神经的适应

吸毒是当今全球性公害。我国2001年登记在册的海洛因依赖者有60.1万，目前吸毒人员仍呈增长的趋势。戒毒治疗是减少需求，减少伤害的有效手段[1，2]，对于海洛因依赖来讲，其核心问题是为什么依赖者由简单的用药发展到强迫性的用药行为？为什么戒断后又很容易回到原有的强迫性用药状态？并随着停药时间的延长，病人用药后的快感逐渐减轻的同时对药物的渴求可以保留或与日俱增。在导致依赖的起初阶段，药物引起的奖赏效应是不断用药的主要动机，而显形性特征，如持续的心理渴求和戒断后复吸行为，涉及到依赖的长程适应[3，4]。海洛因身体依赖…     

单胺类神经递质在药物成瘾中的作用机制

药物成瘾是一种慢性复发性大脑疾病,各种成瘾性药物通过作用于奖赏系统,最终引起神经递质释放的改变,产生奖赏效应。其中,单胺类神经递质5-羟色胺(5-hydroxytryptamine,5-HT)、去甲肾上腺素(noradrenergic,NE)和多巴胺(dopamine,DA)在药物成瘾中起到重要作用,该文就单胺类神经递质在药物成瘾中的作用及机制进行综述。     

5-羟色胺与创伤后应激障碍的研究进展

创伤后应激障碍(posttraumatic stress disorder,PTSD)是当机体遭受威胁生命或者强烈精神创伤后发生的疾病。近年来研究发现,5-羟色胺(5-HT)可能通过5-羟色胺转运体 (SERT)、5-HT受体(主要包括5-HT 1A 、5-HT1B、5-HT2A和5- HT2C受体),以及多巴胺、去甲肾上腺素等神经递质相互作用,参与PTSD的发生,该文就此进行综述。     

脑缺血后谷氨酸及其受体介导的神经细胞损伤及相关药物研究进展

脑缺血损伤涉及多种病理过程,其中兴奋性毒性是关键机制之一。谷氨酸是脑内主要的兴奋性递质,谷氨酸及其受体的病理变化是引起兴奋性毒性的重要病理基础。该文综述了脑缺血后谷氨酸异常释放、谷氨酸受体表达变化及受体后信号传导等病理机制,及以上述机制为靶点的药物研究进展。     

代谢型谷氨酸受体5与神经系统疾病的研究进展

代谢型谷氨酸受体5(mGluR5)作为重要的mGluR之一,通过第二信使发挥生物学效应。mGluR5以二聚体形式主要分布于大脑皮质、海马和纹状体等区域,通过激活磷脂酶C-肌醇1,4,5-三磷酸-甘油二酯-Ca~(2+)和磷脂酰肌醇3-激酶-哺乳动物雷帕霉素靶蛋白等信号通路,参与神经兴奋性网络调节、神经发生以及与学习记忆相关的突触可塑性形成。近来研究证实,mGluR5在神经性疾病中发挥着重要作用。研究表明,mGluR5的过度激活或抑制与多种神经性疾病的病理过程密切相关。多种选择性激活或抑制mGluR5活性的药物已被应用于神经性疾病的治疗。     

抗阿片依赖药物干预的研究进展

人类疾病谱正面临着重大的变化，21世纪上半叶将进入精神疾病时代。在众多的精神疾病中，精神活性物质依赖占有重要位置。其中以阿片类药物造成的滥用最为严重。精神活性物质依赖对国民经济、人口素质和社会安全的危害无法估量。毒瘾是一种病，吸毒者是一类特殊的病人。研究精神活性物质依赖的生物学基础和医学生物学干预手段反应了我国社会和科学发展的重大需求。阿片类毒品危害之所以如此严重主要原因是复发造成的难以戒除，复发主要是由精神依赖引起的，而精神依赖的神经生物学本质又是由于在阿片类毒品长期作用下机体的阿片受体作用系统在受体前、受体上和受体后发生了代偿性适应造成的。目前，在临床上用于脱毒和防复发的医学生物学干预手段主要包括药物干预手段，如激动剂美沙酮、部分激动剂丁丙喏啡和拮抗剂纳曲酮等；生理干预手段，如电针抗复发等。这些干预手段的共同特点都是通过影响阿片受体作用系统的功能实现的。近十多年来，人们逐渐认识到，阿片所导致的代偿性适应不仅和阿片受体作用系统相关，还和多类非阿片受体作用系统密切相关。这些系统至少包括单胺、兴奋性氨基酸、GABA、乙酰胆碱和咪唑啉等受体作用系统。干预这些非阿片受体作用系统的化合物能否成为有效的抗阿片复发药物已成为了本领域新的研究热点。     

The role of metabotropic glutamate receptors in drug reward, motivation and dependence

Addiction to drugs of abuse is a disorder that involves dysfunctions in motivational processes. Both the primary rewarding effects of drugs, as well as the acquired motivational properties of stimuli associated with drug-seeking and -taking, contribute to the perpetuation of dependence on drugs of abuse. Metabotropic glutamate (mGlu) receptors, which mediate slow glutamate neurotransmission, are located throughout limbic and cortical brain sites implicated in drug addiction. Preclinical evidence suggests that mGlu receptors play a crucial role in regulating behavioral effects of drugs of abuse relevant to drug addiction. Specifically, antagonists at excitatory postsynaptic mGlu5 receptors decrease drug self-administration without affecting motor behaviors, cognition or the reward value of natural rewards, while agonists at inhibitory presynaptic mGlu2/3 receptor agonists prevent reinstatement to drug-seeking and -taking after a period of abstinence. These findings have increased our understanding of the neuropathological processes associated with aspects of dependence on drugs of abuse and have provided new targets for pharmacological approaches to the treatment of dysfunctions in motivational processes characterizing the various phases of drug addiction.     

亲代谢型谷氨酸受体和相关神经疾病

谷氨酸的过量释放在多种神经系统疾病的发生发展过程中发挥着重要作用。虽然离子型谷氨酸受体拮抗剂在动物模型中取得了一定的治疗效果,但因其同时阻断了正常的兴奋性传递,限制了这类化合物的临床应用;而mG luR s通过突触前机制抑制谷氨酸的释放,有望成为某些神经系统疾病治疗的新靶点。该文就近年来国内外mG luR s在这些神经疾病中的研究进展作一综述。     

Metabotropic glutamate receptors as drug targets

L-glutamate (Glu), the main excitatory amino acid neurotransmitter in the mammalian central nervous system, is involved in many physiological functions, including learning and memory, but also in toxic phenomena occurring in numerous degenerative or neurological diseases. These functions mainly result from its interaction with Glu receptors (GluRs). The broad spectrum of roles played by glutamate derived from the large number of membrane receptors, which are currently classified in two main categories, ionotropic (iGluRs) and metabotropic (mGluRs) receptors. The iGluRs are ion channels, permeant to Na(+) (Ca(2+)) while the mGluRs belongs to the superfamily of G-protein coupled receptors (GPCRs). Despite continuous efforts over more than two decades, the use of iGluR agonists or antagonists to improve or inhibit excitatory transmission in pathological states still remains a major challenge, though the discovery and development of recent molecules may prove it worthwhile. This probably results form the vital role of fast excitatory transmission in many fundamental physiological functions. Since the discovery of mGluRs, hope has emerged. Indeed, mGluRs are mainly involved in the regulation of fast excitatory transmission. Consequently, it was logically thought that modulating mGluRs with agonists or antagonists might lead to more subtle regulation of fast excitatory transmission than by directly blocking iGluRs. As a result of intensive investigation, new drugs permitting to discriminate between these receptors have emerged. Moreover, a new class of molecules acting as negative or positive allosteric modulators or mGluRs is now available and appears to be promising. In the following, we will review the classification of mGluRs and the functions in which mGluRs are involved. We will focus on their potential as therapeutic targets for improving numerous physiological functions and for different neurodegenerative and neuropsychiatric disorders, which are related to malfunction of Glu signaling in human beings.     

与阿片类药物依赖相关的非阿片受体

药物依赖是药物长期与机体相互作用后引起的一种慢性复发性脑病,其本质是代偿性适应,有多种神经递质受体参与,包括阿片类受体和非阿片类受体,涉及复杂的神经生物学机制,迄今未被完全阐明。自从1973年人们确证体内存在阿片受体以来,国内外对阿片受体进行了大量的研究,明确了它是阿片类药物发挥奖赏的起始作用位点,长期在激动剂的作用下发生代偿性适应。但此后人们发现在药物依赖形成过程中的某些非阿片受体也发生代偿性变化,     

Metabotropic glutamate receptors and interacting proteins: evolving drug targets

The correct targeting, localization, regulation and signaling of metabotropic glutamate receptors (mGluRs) represent major mechanisms underlying the complex function of neuronal networks. These tasks are accomplished by the formation of synaptic signal complexes that integrate functionally related proteins such as neurotransmitter receptors, enzymes and scaffold proteins. By these means, proteins interacting with mGluRs are important regulators of glutamatergic neurotransmission. Most described mGluR interaction partners bind to the intracellular C-termini of the receptors. These domains are extensively spliced and phosphorylated, resulting in a high variability of binding surfaces offered to interacting proteins. Malfunction of mGluRs and associated proteins are linked to neurodegenerative and neuropsychiatric disorders including addiction, depression, epilepsy, schizophrenia, Alzheimer's, Huntington's and Parkinson's disease. MGluR associated signal complexes are dynamic structures that assemble and disassemble in response to the neuronal fate. This, in principle, allows therapeutic intervention, defining mGluRs and interacting proteins as promising drug targets. In the last years, several studies elucidated the geometry of mGluRs in contact with regulatory proteins, providing a solid fundament for the development of new therapeutic strategies. Here, I will give an overview of human disorders directly associated with mGluR malfunction, provide an up-to-date summary of mGluR interacting proteins and highlight recently described structures of mGluR domains in contact with binding partners.     

Metabotropic glutamate 2/3 receptors as drug targets

Metabotropic glutamate receptors are a family of class III G-protein-coupled receptors comprising eight members (mGluR1-8), which are an attractive target in the central nervous system because of the widespread use of glutamate as the principal excitatory amino acid transmitter. The unique pharmacology of class III G-protein coupled receptors, their forebrain localization in key limbic-related cortical/thalamic/striatal/amygdaloid circuits, and the promise of subtle modulation of glutamatergic neurotransmission make these receptors intriguing targets for a wide variety of neuropsychiatric disorders.     

Metabotropic glutamate receptors as targets for new drug development

The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.     

阿片类药物依赖的治疗学进展

介绍阿片类物质依赖的主要药物治疗学进展，主要包括三个步骤，重点介绍阿片受体激动药和非阿片受体激动药的使用，此外尚有非药物疗法及免疫疗法等。